* 190070

KRAS PROTOONCOGENE, GTPase; KRAS


Alternative titles; symbols

V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG
ONCOGENE KRAS2; KRAS2
KIRSTEN MURINE SARCOMA VIRUS 2; RASK2
C-KRAS


Other entities represented in this entry:

V-KI-RAS1 PSEUDOGENE, INCLUDED; KRAS1P, INCLUDED
ONCOGENE KRAS1, INCLUDED; KRAS1, INCLUDED
KIRSTEN RAS1, INCLUDED; RASK1, INCLUDED

HGNC Approved Gene Symbol: KRAS

Cytogenetic location: 12p12.1     Genomic coordinates (GRCh38): 12:25,205,246-25,250,929 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12p12.1 Arteriovenous malformation of the brain, somatic 108010 3
Bladder cancer, somatic 109800 3
Breast cancer, somatic 114480 3
Cardiofaciocutaneous syndrome 2 615278 AD 3
Gastric cancer, somatic 613659 3
Leukemia, acute myeloid, somatic 601626 3
Lung cancer, somatic 211980 3
Noonan syndrome 3 609942 AD 3
Oculoectodermal syndrome, somatic 600268 3
Pancreatic carcinoma, somatic 260350 3
RAS-associated autoimmune leukoproliferative disorder 614470 AD 3
Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 163200 3

TEXT

Description

The KRAS gene encodes the human cellular homolog of a transforming gene isolated from the Kirsten rat sarcoma virus. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers. The most well-studied members of the RAS (derived from 'RAt Sarcoma' virus) gene family include KRAS, HRAS (190020), and NRAS (164790). These genes encode immunologically related proteins with a molecular mass of 21 kD and are homologs of rodent sarcoma virus genes that have transforming abilities. While these wildtype cellular proteins in humans play a vital role in normal tissue signaling, including proliferation, differentiation, and senescence, mutated genes are potent oncogenes that play a role in many human cancers (Weinberg, 1982; Kranenburg, 2005).


Cloning and Expression

Der et al. (1982) identified a new human DNA sequence homologous to the transforming oncogene of the Kirsten (ras-K) murine sarcoma virus within mouse 3T3 fibroblast cells transformed by DNA from an undifferentiated human lung cancer cell line (LX-1). The findings showed that KRAS could act as an oncogene in human cancer.

Chang et al. (1982) isolated clones corresponding to the human cellular KRAS gene from human placental and embryonic cDNA libraries. Two isoforms were identified, designated KRAS1 and KRAS2. KRAS1 contained 0.9 kb homologous to viral Kras and had 1 intervening sequence, and KRAS2 contained 0.3 kb homologous to viral Kras. McCoy et al. (1983) characterized the KRAS gene isolated from a human colon adenocarcinoma cell line (SW840) and determined that it corresponded to KRAS2 as identified by Chang et al. (1982). The KRAS2 oncogene was amplified in several tumor cell lines.

McGrath et al. (1983) cloned the KRAS1 and KRAS2 genes and determined that the KRAS1 gene is a pseudogene. The KRAS2 gene encodes a 188-residue protein with a molecular mass of 21.66 kD. It showed only 6 amino acid differences from the viral gene. Comparison of the 2 KRAS genes showed that KRAS1 is lacking several intervening sequences, consistent with it being a pseudogene derived from a processed KRAS2 mRNA. The major KRAS2 mRNA transcript is 5.5 kb. Alternative splicing results in 2 variants, isoforms A and B, that differ in the C-terminal region.

Alternative splicing of exon 5 results in the KRASA and KRASB isoforms. Exon 6 contains the C-terminal region in KRASB, whereas it encodes the 3-prime untranslated region in KRASA. The differing C-terminal regions of these isoforms are subjected to posttranslational modifications. The differential posttranslational processing has profound functional effects leading to alternative trafficking pathways and protein localization (Carta et al., 2006).

Tsai et al. (2015) noted that the use of alternative fourth exons generates 2 KRAS variants, KRAS4A and KRAS4B, the produce isoforms with distinct membrane-targeting sequences. Using confocal microscopy, Tsai et al. (2015) showed that GFP-tagged KRAS4A localized exclusively to the plasma membrane (PM) of HEK293 cells. Palmitoylation of cys180 in the hypervariable region of KRAS4A was required for efficient targeting of KRAS4A to the PM, but a second signal could target KRAS4A to the PM in the absence of cys180 palmitoylation. The authors identified a C-terminal polybasic region in KRAS4A with 2 clusters of positively charged residues (PB1 and PB2). They found that both palmitoylation and PB2 were required for efficient targeting of KRAS4A to the PM. RT-PCR analysis showed that KRAS4A was expressed in all human cancer cell lines examined, especially in colorectal carcinoma and melanoma cell lines.


Gene Structure

McGrath et al. (1983) first reported that the KRAS2 gene spans 38 kb and contains 4 exons. Detailed sequence analysis showed that exon 4 has 2 forms, which the authors designated 4A and 4B.

The KRAS2 gene has been shown to have a total of 6 exons. Exons 2, 3, and 4 are invariant coding exons, whereas exon 5 undergoes alternative splicing. KRASB results from exon 5 skipping. In KRASA mRNA, exon 6 encodes the 3-prime untranslated region. In KRASB mRNA, exon 6 encodes the C-terminal region (Carta et al., 2006).


Mapping

By in situ hybridization, Popescu et al. (1985) mapped the KRAS2 gene to chromosome 12p12.1-p11.1. By linkage with RFLPs, O'Connell et al. (1985) confirmed the approximate location of KRAS2 on 12p12.1.

Pseudogene

The KRAS1 gene is a KRAS2 pseudogene and has been assigned to chromosome 6 (O'Brien et al., 1983; McBride et al., 1983). By in situ hybridization, Popescu et al. (1985) assigned the KRAS1 gene to 6p12-p11. Because KRAS1 was found to be a pseudogene, its official symbol was changed to KRAS1P.


Gene Function

Johnson et al. (2005) found that the 3 human RAS genes, HRAS, KRAS, and NRAS, contain multiple let-7 (605386) complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer.

Bivona et al. (2006) found that the subcellular localization and function of Kras in mammalian cells was modulated by Pkc (see 176960). Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl (BCL2L1; 600039). Phosphorylated Kras required Bclxl for induction of apoptosis.

Yeung et al. (2006) devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS, RAC1 (602048), and c-SRC (190090) that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis.

Heo et al. (2006) surveyed plasma membrane targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that were localized to the plasma membrane, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids, Heo et al. (2006) developed a chemical phosphatase activation method to deplete plasma membrane phosphatidylinositol 4,5-bisphosphate. Unexpectedly, proteins with polybasic clusters dissociated from the plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that both lipid second messengers jointly regulate plasma membrane targeting.

Gazin et al. (2007) performed a genomewide RNA interference (RNAi) screen in KRAS-transformed NIH 3T3 cells and identified 28 genes required for RAS-mediated epigenetic silencing of the proapoptotic FAS gene (TNFRSF6; 134637). At least 9 of these RAS epigenetic silencing effectors (RESEs), including the DNA methyltransferase DNMT1 (126375), were directly associated with specific regions of the FAS promoter in KRAS-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to recruit DNMT1 to the FAS promoter, loss of FAS promoter hypermethylation, and derepression of FAS expression. Analysis of 5 other epigenetically repressed genes indicated that RAS directs the silencing of multiple unrelated genes through a largely common pathway. Finally, Gazin et al. (2007) showed that 9 RESEs are required for anchorage-independent growth and tumorigenicity of KRAS-transformed NIH 3T3 cells; these 9 genes had not previously been implicated in transformation by RAS. Gazin et al. (2007) concluded that RAS-mediated epigenetic silencing occurs through a specific, complex pathway involving components that are required for maintenance of a fully transformed phenotype.

Haigis et al. (2008) used genetically engineered mice to determine whether and how the related oncogenes Kras and Nras (164790) regulate homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek (see 176872)-dependent manner. Nras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc (611731)-mutant colonic tumor, activation of Kras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This Kras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant Kras were hypersensitive to inhibition of Raf (see 164760) but not Mek. Haigis et al. (2008) concluded that their studies demonstrated clear phenotypic differences between mutant Kras and Nras, and suggested that the oncogenic phenotype of mutant Kras might be mediated by noncanonical signaling through Ras effector pathways.

By studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF (164757) genes, Yun et al. (2009) found that GLUT1 (138140), encoding glucose transporter-1, was 1 of 3 genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wildtype KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Yun et al. (2009) concluded that, taken together, these data suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.

Meylan et al. (2009) showed that the NF-kappa-B (see 164011) pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (191170) and expression of oncogenic Kras containing the G12D mutation resulted in NF-kappa-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B signaling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or after tumor progression, resulted in significantly reduced tumor development. Meylan et al. (2009) concluded that, together, their results indicated a critical function for NF-kappa-B signaling in lung tumor development and, further, that this requirement depends on p53 status.

Barbie et al. (2009) used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the noncanonical I-kappa-B kinase TBK1 (604834) was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic signals involving c-REL (164910) and BCLXL (BCL2L1; 600039) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. Barbie et al. (2009) concluded that TBK1 and NF-kappa-B signaling are essential in KRAS mutant tumors, and establish a general approach for the rational identification of codependent pathways in cancer.

In Drosophila eye-antennal discs, cooperation between Ras(V12), an oncogenic form of the Ras85D protein, and loss-of-function mutations in the conserved tumor suppressor 'scribble' (607733) gives rise to metastatic tumors that display many characteristics observed in human cancers (summary by Wu et al., 2010). Wu et al. (2010) showed that clones of cells bearing different mutations can cooperate to promote tumor growth and invasion in Drosophila. The authors found that the Ras(V12) and scrib-null mutations can also cause tumors when they affect different adjacent epithelial cells. Wu et al. (2010) showed that this interaction between Ras(V12) and scrib-null clones involves JNK signaling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines (see 604260), a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumors can also be triggered by tissue damage, a stress condition that activates JNK signaling. The authors suggested that similar cooperative mechanisms could have a role in the development of human cancers.

Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDE-delta (PDED; 602676), which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm (Chandra et al., 2012; Zhang et al., 2004). Zimmermann et al. (2013) reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS.

Yun et al. (2015) found that cultured human colorectal cancer cells harboring KRAS or BRAF (164757) mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 (138140) glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wildtype cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. Yun et al. (2015) suggested that their results provided a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.

Using coexpression analysis, Tsai et al. (2015) showed that, unlike KRAS4B, KRAS4A did not bind PDE6-delta, even though KRAS4A and KRAS4B had identical steady-state localizations at the PM. Further analysis revealed that both membrane-targeting signals of KRAS4A supported its downstream signaling, and that either of the 2 was sufficient for signal output.

Yao et al. (2019) developed an unbiased functional target discovery platform to query oncogeneic KRAS-dependent changes of the pancreatic ductal adenocarcinoma surfaceome, which revealed syndecan-1 (SDC1; 186355) as a protein that is upregulated at the cell surface by oncogenic KRAS. Localization of SDC1 at the cell surface, where it regulates macropinocytosis, an essential metabolic pathway that fuels pancreatic ductal adenocarcinoma cell growth, is essential for disease maintenance and progression.

Amendola et al. (2019) reported a direct, GTP-dependent interaction between the KRAS exon 4A-specific isoform KRAS4A and hexokinase-1 (HK1; 142600) that alters the activity of the kinase, and thereby established that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.

Regulation of KRAS Expression by KRAS1P Transcript Levels

Following their finding that PTENP1 (613531), a pseudogene of the PTEN (601728) tumor suppressor gene, can derepress PTEN by acting as a decoy for PTEN-targeting miRNAS, Poliseno et al. (2010) extended their analysis to the oncogene KRAS and its pseudogene KRAS1. KRAS1P 3-prime UTR overexpression in DU145 prostate cancer cells resulted in increased KRAS mRNA abundance and accelerated cell growth. They also found that KRAS and KRAS1P transcript levels were positively correlated in prostate cancer. Notably, the KRAS1P locus 6p12-p11 is amplified in different human tumors, including neuroblastoma, retinoblastoma, and hepatocellular carcinoma. Poliseno et al. (2010) concluded that their findings together pointed to a putative protooncogenic role for KRAS1P, and supported the notion that pseudogene functions mirror the functions of their cognate genes as explained by a miRNA decoy mechanism.


Molecular Genetics

Role in Solid Tumors

KRAS is said to be one of the most activated oncogenes, with 17 to 25% of all human tumors harboring an activating KRAS mutation (Kranenburg, 2005). Critical regions of the KRAS gene for oncogenic activation include codons 12, 13, 59, 61, and 63 (Grimmond et al., 1992). These activating mutations cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase activating proteins (Zenker et al., 2007).

In a study of 96 human tumors or tumor cell lines in the NIH 3T3 transforming system, Pulciani et al. (1982) found a mutated HRAS locus only in a single cancer cell line, whereas transforming KRAS genes were identified in 8 different carcinomas and sarcomas. KRAS appeared to be involved in malignancy much more often than HRAS. In a serous cystadenocarcinoma of the ovary (167000), Feig et al. (1984) showed the presence of an activated KRAS oncogene that was not activated in normal cells of the same patient. The transforming gene product displayed an electrophoretic mobility pattern that differed from that of KRAS transforming proteins in other tumors, suggesting a novel somatic KRAS mutation in this tumor.

In a cell line of human lung cancer (211980), Nakano et al. (1984) identified a mutation in the KRAS2 gene (190070.0001), resulting in gene activation with transforming ability of the mutant protein.

Rodenhuis et al. (1987) used a novel, highly sensitive assay based on oligonucleotide hybridization following in vitro amplification to examine DNA from 39 lung tumor specimens. The KRAS gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No HRAS, KRAS, or NRAS mutations were observed in 15 squamous cell carcinomas, 10 large cell carcinomas, 1 carcinoid tumor, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small cell carcinoma. An approximately 20-fold amplification of the unmutated KRAS gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma.

Yanez et al. (1987) found mutations in codon 12 of the KRAS gene in 4 of 16 colon cancers (114500), 2 of 27 lung cancers, and 1 of 8 breast cancers (114480); no mutations were found at codon position 61.

The highest observed frequency of KRAS2 point mutations occurs in pancreatic carcinomas (260350), with 90% of the patients having at least 1 KRAS2 mutation (Almoguera et al., 1988; Smit et al., 1988). Most of these mutations are in codon 12 (see, e.g., G12D, 190070.0005 and G12V, 190070.0006) (Hruban et al., 1993).

Burmer and Loeb (1989) identified KRAS2 mutations in both diploid and aneuploid cells in colon adenomas and carcinomas. Twenty-six of 40 colon carcinomas contained mutations at codon 12, and 9 of the 12 adenomas studied contained similar mutations.

Sidransky et al. (1992) found that KRAS mutations were detectable in DNA purified from stool in 8 of 9 patients with colorectal tumors that contained KRAS mutations. Takeda et al. (1993) used a mutant-allele-specific amplification (MASA) method to detect KRAS mutations in cells obtained from the sputum of patients with lung cancer. A mutation was found in 1 of 5 patients studied. The authors suggested that the MASA system could be applied to an examination of metastatic lung carcinomas, particularly from adenocarcinomas of the colon and pancreas in which KRAS mutations are frequently detected, and to mass screening for colorectal tumors, using DNA isolated from feces as a template.

Lee et al. (1995) identified mutations in codon 12 of the KRAS gene in 11 (7.9%) of 140 gastric cancers (613659). Seven cases had a G12S mutation (190070.0007) and 2 had a G12D mutation (190070.0005). Tumors located in the upper third of the stomach had a significantly higher frequency of KRAS codon 12 mutations (3 of 8; 37.5%) compared with tumors located in the middle (4 of 29; 13.8%) or lower (3 of 99; 3%) thirds of the stomach (P = 0.001). Among 8 patients with stomach cancer located in the upper part of the stomach, death occurred in 4 of 5 patients with tumors without KRAS gene mutations, but in none of the 3 patients with KRAS gene-mutated tumors.

Otori et al. (1997) examined tissue sections from 19 hyperplastic colorectal polyps for mutations in exons 12 and 13 of the KRAS gene. KRAS mutations were detected in 9 (47%) of 19 polyps, suggesting that some hyperplastic colorectal polyps may be true premalignant lesions.

KRAS activation has been recognized in microdissected foci of pancreatic intraepithelial neoplasia (Cubilla and Fitzgerald, 1976; Hruban et al., 2000; Hruban et al., 2000), the candidate precursor lesion of pancreatic cancer previously known as ductal cell hyperplasia. Laghi et al. (2002) found that KRAS codon 12 was mutated in 34 of 41 (83%) pancreatic cancers and in 11 of 13 (85%) biliary cancers. Multiple distinct KRAS mutations were found in 16 pancreatic cancers and in 8 biliary cancers. Multiple KRAS mutations were more frequent in cancers with detectable pancreatic intraepithelial neoplasia than in those without, and individual precursor lesions of the same neoplastic pancreas harbored distinct mutations. The results indicated that clonally distinct precursor lesions of pancreatic cancer may variably contribute to tumor development.

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular (188470) and Hurthle cell (607464) thyroid tumors for HRAS, NRAS, or KRAS mutations and PAX8 (167415)-PPARG (601487) rearrangements. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.

Rajagopalan et al. (2002) systematically evaluated mutations in the BRAF (164757) and KRAS genes in 330 colorectal tumors. There were 32 mutations in BRAF and 169 mutations in KRAS; no tumor exhibited mutations in both BRAF and KRAS. Rajagopalan et al. (2002) concluded that BRAF and KRAS mutations are equivalent in their tumorigenic effects and are mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. Kim et al. (2003) found 7 KRAS missense mutations in 66 gastric cancers and 16 gastric cancer cell lines. No BRAF mutations were found.

Oliveira et al. (2004) investigated KRAS in 158 hereditary nonpolyposis colorectal cancer (HNPCC2; 609310) tumors from patients with germline MLH1 (120436), MSH2 (609309) or MSH6 (600678) mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancers were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D (190070.0003) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02) or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. The authors concluded that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status) and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway.

Sommerer et al. (2005) analyzed the KRAS gene in 30 seminomas and 32 nonseminomatous GCTs (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations, all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%) of 32 nonseminomas.

Groesser et al. (2012) identified somatic mutations in the KRAS gene (G12D, 190070.0005 and G12V, 190070.0006) in 3 (5%) of 65 nevus sebaceous tumors (see 162900). The G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200). The authors postulated that the mosaic mutation likely extends to extracutaneous tissues in the latter disorder, which could explain the phenotypic pleiotropy.

Vermeulen et al. (2013) quantified the competitive advantage in tumor development of Apc (611731) loss, Kras activation, and p53 (191170) mutations in the mouse intestine. Their findings indicated that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wildtype stem cells after biased but still stochastic events. Furthermore, Vermeulen et al. (2013) found that p53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene were favored. Vermeulen et al. (2013) concluded that their work confirmed the notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.

Hematologic Malignancies

The myelodysplastic syndrome is a preleukemic hematologic disorder characterized by low blood counts, bone marrow cells of abnormal appearance, and progression to acute leukemia in as many as 30% of patients. Liu et al. (1987) identified a transforming allele in the KRAS gene in 2 of 4 patients with preleukemia and in 1 who progressed to acute leukemia from myelodysplastic syndrome. In 1 preleukemic patient, they detected a novel mutation in codon 13 of KRAS in bone marrow cells harvested 1.5 years before the acute leukemia developed. The findings provided evidence that RAS mutations may be involved in the early stages of human leukemia.

In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; 601626), Bollag et al. (1996) identified a somatic in-frame 3-bp insertion in the KRAS gene (190070.0008).

Bezieau et al. (2001) used ARMS (allele-specific amplification method) to evaluate the incidence of NRAS- and KRAS2-activating mutations in patients with multiple myeloma (254500) and related disorders. Mutations were more frequent in KRAS2 than in NRAS. The authors concluded that early mutations in these 2 oncogenes may play a major role in the oncogenesis of multiple myeloma and primary plasma cell leukemia.

In white blood cells derived from 3 unrelated girls with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, 190070.0003; G12D, 190070.0005; and G12S, 190070.0007). The patients were ascertained from a cohort of 80 children with JMML.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the NRAS (164790) or KRAS genes in 23/200 (12%) samples.

RAS-Associated Autoimmune Leukoproliferative Disorder

In 2 unrelated girls with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, 190070.0005 and G13C, 190070.0023). The patients presented in early childhood with lymphadenopathy, splenomegaly, and autoimmune disorders. One patient had recurrent infections. In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM (BCL2L11; 603827) and facilitated lymphocyte proliferation through downregulation of CDKN1B (600778).

Cardiofaciocutaneous Syndrome, Noonan Syndrome 3, and Costello Syndrome

Cardiofaciocutaneous (CFC) syndrome (see 115150) is characterized by distinctive facial appearance, heart defects, and mental retardation. CFC shows phenotypic overlap with Noonan syndrome (see 163950) and Costello syndrome (218040). Approximately 40% of individuals with clinically diagnosed Noonan syndrome have gain-of-function mutations in protein-tyrosine phosphatase SHP2 (PTPN11; 176876). Aoki et al. (2005) identified mutations in the HRAS gene in 12 of 13 individuals with Costello syndrome, suggesting that the activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome, Costello syndrome, and possibly CFC syndrome. In 2 of 43 unrelated individuals with CFC syndrome (CFC2; 615278), Niihori et al. (2006) identified different heterozygous KRAS mutations (G60R, 190070.0009 and D153V, 190070.0010). Neither mutation had previously been identified in individuals with cancer. In the same study, Niihori et al. (2006) found 8 different mutations in the BRAF gene (164757), an isoform in the RAF protooncogene family, in 16 of 40 individuals with CFC syndrome.

Schubbert et al. (2006) identified 3 de novo germline KRAS mutations (190070.0010-190070.0012) in 5 individuals with Noonan syndrome-3 (NS3; 609942).

In 2 individuals exhibiting a severe Noonan syndrome-3 phenotype with features overlapping those of CFC and Costello syndromes, Carta et al. (2006) identified 2 different heterozygous KRAS mutations (190070.0014 and 190070.0015). Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor.

Zenker et al. (2007) identified 11 different germline mutations in the KRAS gene, including 8 novel mutations, in a total of 12 patients with a clinical diagnosis of CFC (2), Noonan syndrome-3 (7), CFC/Noonan syndrome overlap (1), or Costello syndrome (2). All patients showed mild to moderate mental retardation. The 2 unrelated infants with Costello syndrome had 2 different heterozygous mutations (190070.0017-190070.0018). Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. Zenker et al. (2007) noted that these patients may later develop features of CFC syndrome, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these diverse but phenotypically related disorders.

In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, Bertola et al. (2007) identified a mutation in the KRAS gene (K5E; 190070.0019). The authors noted that this mutation was in the same codon as that of 1 of the patients reported by Zenker et al. (2007) (K5N; 190070.0017).

Schulz et al. (2008) identified mutations in the KRAS gene in 3 (5.9%) of 51 CFC patients.

Development of Resistance to Chemotherapeutic Agents

Misale et al. (2012) showed that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR (131550) treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. Misale et al. (2012) concluded that their results identified KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicated that the emergence of KRAS mutant clones can be detected noninvasively months before radiographic progression, and suggested early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

Diaz et al. (2012) determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of 24 (38%) patients whose tumors were initially KRAS wildtype developed detectable mutations in KRAS in their sera, 3 of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modeling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. Diaz et al. (2012) suggested that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a noninvasive manner. The results also explained why solid tumors develop resistance to targeted therapies in a highly reproducible fashion.

Arteriovenous Malformations of the Brain

Nikolaev et al. (2018) analyzed tissue and blood samples from patients with arteriovenous malformations of the brain (BAVM; 108010) to detect somatic mutations. They performed exome DNA sequencing of BAVM tissue samples from 26 patients in the main study group and of paired blood samples from 17 of these patients, and then confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. Nikolaev et al. (2018) detected somatic activating KRAS mutations gly12 to asp (G12D; 190070.0025) and gly12 to val (G12V; 190070.0026) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, Nikolaev et al. (2018) detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (190198) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see 176872). Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells.

Oculoectodermal Syndrome

In affected tissue from 2 patients with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) identified somatic mosaicism for 2 different missense mutations in the KRAS gene, G12D (190070.0003) and L19F (190070.0024).

In 3 unrelated children with OES, Boppudi et al. (2016) identified somatic missense mutations in the KRAS gene, A146T (190070.0027) and A146V (190070.0028), that were mosaic in lesional tissue and absent from leukocyte DNA.

In a 4-year-old Mexican girl (patient 1) and an unrelated 12-year-old Mexican boy (patient 2) with OES, Chacon-Camacho et al. (2019) identified somatic mosaicism for the previously reported KRAS variants, A146T and A146V, respectively.

Associations Pending Confirmation

For discussion of a possible association between postzygotic somatic mutation in the KRAS gene and melorheostosis, see 166700.


Genotype/Phenotype Correlations

Andreyev et al. (1997) used PCR amplification and DNA sequencing to investigate KRAS exon 1 mutations (codons 12 and 13) in histologic sections of colorectal adenocarcinomas. They examined samples from 98 patients with Dukes stage A or B fully resected colorectal cancers. Fourteen of these patients had subsequently relapsed. The presence of a KRAS mutation was not associated with tumor stage or histologic grade; neither was there any association with those patients who relapsed. The authors concluded that detection of KRAS mutation in early colorectal adenocarcinomas was of no prognostic value.

Porta et al. (1999) found that serum concentrations of organochlorine compounds were significantly higher in patients with exocrine pancreatic cancer with a codon 12 KRAS2 mutation compared to cases without a mutation, with an odds ratio of 8.7 for one organochlorine and 5.3 for another organochlorine. These estimates held after adjusting for total lipids, other covariates, and total polychlorinated biphenyls (PCBs). A specific association was observed between the G12V (190070.0006) mutation and both organochlorine concentrations, with an odds ratio of 15.9 and 24.1 for each of the compounds. A similar pattern was shown for the major diorthochlorinated PCBs.

Vasko et al. (2003) performed a pooled analysis of 269 mutations in HRAS, KRAS, and NRAS garnered from 39 previous studies of thyroid tumors. Mutations in codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary tumors (see 188550) (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of the study by Vasko et al. (2003) involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and in 1 follicular carcinoma (2.9%). Mutations in codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively.


Population Genetics

Although several studies confirmed that approximately 40% of primary colorectal adenocarcinomas in humans contain a mutated form of the KRAS2 gene, the patterns of mutation at codons 12, 13, and 61 are not the same in different populations. Hayashi et al. (1996) used the MASA method to analyze the frequency and type of point mutations in these 3 codons in 319 colorectal cancer tissues collected from patients in Japan. They then compared these results with those from other sources to examine whether different geographic locations and environmental influences might impose distinct patterns on the spectrum of KRAS mutations. Comparing findings in the U.S., France, and Yugoslavia with those in Japan, a number of significant differences were found. A possible explanation put forth by Hayashi et al. (1996) was that an environmental carcinogen prevailing in a geographic region combines with the susceptibility of a particular tissue to dictate which type of DNA lesion will predominate. The predominance of G-to-A mutations among American and Japanese colorectal cancer patients could be attributable to alkylating agents or to the absence of direct interaction with any carcinogens. The prevalence of G-to-T mutations among Yugoslav and French patients might be ascribed to polycyclic aromatic hydrocarbons and heterocyclic amines.


Animal Model

Muller et al. (1983) found transcription of KRAS and the McDonough strain of feline sarcoma virus (FMS) gene (see 164770) during mouse development. Furthermore, the differences in transcription in different tissues suggested a specific role for each: FMS was expressed in extraembryonic structures or in transport in these tissues, whereas KRAS was expressed ubiquitously.

Holland et al. (2000) transferred, in a tissue-specific manner, genes encoding activated forms of Ras and Akt (164730) to astrocytes and neural progenitors in mice. Although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme (GBM; 137800) formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and Holland et al. (2000) demonstrated that AKT activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease.

Johnson et al. (2001) used a variation of 'hit-and-run' gene targeting to create mouse strains carrying oncogenic alleles of Kras capable of activation only on a spontaneous recombination event in the whole animal. They demonstrated that mice carrying these mutations were highly predisposed to a range of tumor types, predominantly early-onset lung cancer. This model was further characterized by examining the effects of germline mutations in the p53 gene (191170), which is known to be mutated along with KRAS in human tumors. Johnson et al. (2001) concluded that their approach had several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

Zhang et al. (2001) presented evidence of a tumor suppressor role of wildtype KRAS2 in lung tumorigenesis. They found that heterozygous Kras2-deficient mice were highly susceptible to the chemical induction of lung tumors compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells. Allelic loss of wildtype Kras2 was found in 67 to 100% of chemically induced mouse lung adenocarcinomas that harbored a mutant Kras2 allele. These and other data strongly suggested that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression. Pfeifer (2001) commented on these findings as representing 'a new verdict for an old convict.' He quoted evidence that the HRAS1 gene may also function as a tumor suppressor. Pfeifer (2001) noted an interesting parallel to the p53 tumor suppressor, which was initially described as an oncogene, carrying point mutations in tumors. Later it was discovered that it is, in fact, the wildtype copy of the gene that functions as a tumor suppressor gene and is capable of reducing cell proliferation.

Costa et al. (2002) crossed Nf1 (613113) heterozygote mice with mice heterozygous for a null mutation in the Kras gene. Double heterozygotes with decreased Ras function had improved learning relative to Nf1 heterozygote mice. Costa et al. (2002) also showed that the Nf1 +/- mice have increased GABA-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Costa et al. (2002) concluded that learning deficits associated with Nf1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition.

An S17N substitution in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, Matallanas et al. (2003) found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts.

By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, Dinulescu et al. (2005) expressed an oncogenic Kras allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma (167000); 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary.

Collado et al. (2005) used a mouse model for cancer initiation in humans: the animals had a conditional oncogenic K-rasV12 (190070.0006) allele that is activated only by the enzyme Cre recombinase, causing them to develop multiple lung adenomas (premalignant tumors) and a few lung adenocarcinomas (malignant tumors). Senescence markers previously identified in cultured cells were used to detect oncogene-induced senescence in lung sections from control mice (expressing Cre) and from K-rasV12-expressing mice (expressing Cre and activated K-rasV12). Collado et al. (2005) analyzed p16(INK4a) (600160), an effector of in vitro oncogene-induced senescence, and de novo markers that were identified by using DNA microarray analysis of in vitro oncogene-induced senescence. These de novo markers are p15(INK4b), also known as CDKN2B (600431), DEC1 (BHLHB2; 604256), and DCR2 (TNFRSF10D; 603614). Staining with antibodies against p16(INK4a), p15(INK4b), DEC1, and DCR2 revealed abundant positive cells in adenomas, whereas adenocarcinomas were essentially negative. By contrast, the proliferation marker Ki-67 revealed a weak proliferative index in adenomas compared with adenocarcinomas. Collado et al. (2005) concluded that oncogene-induced senescence may help to restrict tumor progression. They concluded that a substantial number of cells in premalignant tumors undergo oncogene-induced senescence, but that cells in malignant tumors are unable to do this owing to the loss of oncogene-induced senescence effectors such as p16(INK4a) or p53.

Using an Hras (190020) knockin mouse model, To et al. (2008) demonstrated that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target Ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications. To et al. (2008) concluded that their findings may have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.

Junttila et al. (2010) modeled the probable therapeutic impact of p53 (191170) restoration in a spontaneously evolving mouse model of nonsmall cell lung cancer (NSCLC) initiated by sporadic oncogenic activation of endogenous KRAS developed by Jackson et al. (2001). Surprisingly, p53 restoration failed to induce significant regression of established tumors, although it did result in a significant decrease in the relative proportion of high-grade tumors. This was due to selective activation of p53 only in the more aggressive tumor cells within each tumor. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signaling sensor p19(ARF) (600160). Junttila et al. (2010) concluded that p53-mediated tumor suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumor evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

A single endogenous mutant Kras allele is sufficient to promote lung tumor formation in mice, but malignant progression requires additional genetic alterations. Junttila et al. (2010) showed that advanced lung tumors from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) (see 190070.0005) allelic enrichment (Kras(G12D)/Kras(wildtype) greater than 1), implying that mutant Kras copy gains are positively selected during progression. Through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, Kerr et al. (2016) demonstrated that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channeling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous nonsmall cell lung cancer cells and in vivo, and in spontaneous advanced murine lung tumors (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumors (Kras(G12D) heterozygous). Finally, Kerr et al. (2016) demonstrated that mutant Kras copy gain creates unique metabolic dependencies that can be exploited to selectively target these aggressive mutant Kras tumors. The authors concluded that mutant Kras lung tumors are not a single disease but rather a heterogeneous group comprising 2 classes of tumors with distinct metabolic profiles, prognosis, and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content.


ALLELIC VARIANTS ( 28 Selected Examples):

.0001 LUNG CANCER, SOMATIC

KRAS, GLY12CYS
  
RCV000013406...

In a cell line of human lung cancer (211980), Nakano et al. (1984) identified a 34G-T transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-cys (G12C) substitution. Studies of the mutant protein showed that it had transforming abilities consistent with activation of the gene.

In a study of 106 prospectively enrolled patients with primary adenocarcinoma of the lung, Ahrendt et al. (2001) found that 92 (87%) were smokers. KRAS2 mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS2 mutations had 1 of 4 changes in codon 12, the most common being G12C, which was present in 25 tumors.

Inhibitor of KRAS(G12C)

Canon et al. (2019) optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity to knockdown KRAS carrying the G12C variant. Canon et al. (2019) discovered the KRAS(G12C) inhibitor AMG-510 and presented data on its preclinical activity. Treatment with AMG-510 led to the regression of KRAS(G12C) tumors and improved the antitumor efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG-510 resulted in a proinflammatory tumor microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS(G12D) tumors, which suggested adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG-510 demonstrated antitumor activity in the first dosing cohorts and represented a potentially transformative therapy for patients for whom effective treatments are lacking.

Janne et al. (2022) conducted a phase 2 cohort study to evaluate the clinical efficacy of oral adagrasib, a selective covalent KRAS(G12C) inhibitor, among patients with KRAS(G12C)-mutated nonsmall cell lung cancer who were previously treated with platinum-based chemotherapy and antiprogrammed death 1 or programmed ligand 1 therapy. Among the 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response by blinded independent review. The median duration of response was 8.5 months, with a median progression-free survival of 6.5 months and median overall survival of 12.6 months at last follow-up. Treatment-related adverse events of grade 3 or higher occurred in 44.8%, resulting in a treatment discontinuation rate of 6.9%.


.0002 LUNG CANCER, SQUAMOUS CELL, SOMATIC

BLADDER CANCER, SOMATIC, INCLUDED
KRAS, GLY12ARG
  
RCV000013407...

In a squamous cell lung carcinoma (211980) from a 66-year-old man, Santos et al. (1984) identified a G-to-C transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-arg (G12R) substitution. The mutation was not identified in the patient's normal bronchial and pulmonary parenchymal tissues or blood lymphocytes. This mutation had previously been identified in a bladder cancer (109800) and a lung cancer.


.0003 BREAST ADENOCARCINOMA, SOMATIC

JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED
OCULOECTODERMAL SYNDROME, SOMATIC, INCLUDED
KRAS, GLY13ASP
  
RCV000013409...

Breast Adenocarcinoma, Somatic

In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein.

Juvenile Myelomonocytic Leukemia, Somatic

In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene.

RAS-associated Autoimmune Leukoproliferative Disorder, Somatic

In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired.

Oculoectodermal Syndrome

In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood.


.0004 BLADDER CANCER, TRANSITIONAL CELL, SOMATIC

KRAS, ALA59THR
  
RCV000013410...

In a human transitional cell bladder carcinoma cell line (109800), Grimmond et al. (1992) identified a heterozygous G-to-A transition in the KRAS2 gene, resulting in an ala59-to-thr (A59T) substitution. The mutation was present in paraffin-embedded tissue from the primary tumor of the patient.


.0005 PANCREATIC CARCINOMA, SOMATIC

GASTRIC CANCER, SOMATIC, INCLUDED
EPIDERMAL NEVUS, SOMATIC, INCLUDED
NEVUS SEBACEOUS, SOMATIC, INCLUDED
SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED
JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED
KRAS, GLY12ASP
  
RCV000013411...

Pancreatic Carcinoma, Somatic

Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.

Gastric Cancer, Somatic

Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.

Epidermal Nevus, Somatic

Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.

Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.

Nevus Sebaceous, Somatic

Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).

Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic

The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.

Juvenile Myelomonocytic Leukemia, Somatic

In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.

RAS-associated Autoimmune Leukoproliferative Disorder, Somatic

In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene.


.0006 PANCREATIC CARCINOMA, SOMATIC

NEVUS SEBACEOUS, SOMATIC, INCLUDED
KRAS, GLY12VAL
  
RCV000013413...

Pancreatic Carcinoma, Somatic

For discussion of the gly12-to-val (G12V) substitution that was found in 1 of 53 pancreatic carcinomas (260350) by Motojima et al. (1993), see 190070.0005.

Nevus Sebaceous, Somatic

Groesser et al. (2012) identified a somatic G12V mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900). The tumor also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).


.0007 GASTRIC CANCER, SOMATIC

JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
KRAS, GLY12SER
  
RCV000013414...

Gastric Cancer, Somatic

Lee et al. (1995) found mutations in codon 12 of the KRAS2 gene in 9 of 140 cases of gastric cancer (613659); 7 cases had a G-to-A transition, resulting in a gly12-to-ser (G12S) substitution.

Juvenile Myelomonocytic Leukemia, Somatic

In white blood cells derived from a 4-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12S mutation in the KRAS gene.


.0008 LEUKEMIA, ACUTE MYELOGENOUS, SOMATIC

KRAS, 3-BP INS, GLY11INS
  
RCV000013415

In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; 601626), Bollag et al. (1996) identified an in-frame 3-bp insertion in exon 1 of the KRAS2 gene, resulting in an insertion of gly11. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the RAS-mitogen-activated protein kinase signaling pathway. RAS-GTP levels measured in COS cells established that this novel mutant accumulates up to 90% in the GTP state, considerably higher than a residue 12 mutant. This mutation was the first dominant RAS mutation found in human cancer that did not involve residues 12, 13, or 61.


.0009 CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, GLY60ARG
  
RCV000013416...

In an individual with cardiofaciocutaneous syndrome (CFC2; 615278), Niihori et al. (2006) identified a heterozygous 178G-C transversion in exon 2 of the KRAS2 gene, predicting a gly60-to-arg (G60R) substitution.


.0010 CARDIOFACIOCUTANEOUS SYNDROME 2

NOONAN SYNDROME 3, INCLUDED
KRAS, ASP153VAL
  
RCV000013417...

Cardiofaciocutaneous Syndrome 2

In 2 unrelated individuals with cardiofaciocutaneous syndrome (CFC2; 615278), Niihori et al. (2006) identified a heterozygous 458A-T transversion in exon 4b of the KRAS2 gene, predicting an asp153-to-val (D153V) substitution. The D153V mutation was identified in DNA extracted from both blood and buccal cells of 1 of the individuals. This heterozygous mutation and G60R (190070.0009) were not found in 100 control chromosomes and were not found in any parent. The results suggested that these germline mutations occurred de novo.

Noonan Syndrome 3

Schubbert et al. (2006) found the D153V mutation in a patient who had been diagnosed with Noonan syndrome-3 (NS3; 609942). The 18-year-old male had hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse, Noonan-like features, short stature, mild pectus carinatum, unilateral cryptorchidism, mild developmental delay, and grand mal seizures.


.0011 NOONAN SYNDROME 3

KRAS, THR58ILE
  
RCV000013419...

In a 3-month-old female with Noonan syndrome-3 (NS3; 609942), Schubbert et al. (2006) identified a heterozygous 173C-T transition in the KRAS2 gene, resulting in a thr58-to-ile (T58I) substitution. The child had a severe clinical phenotype and presented with a myeloproliferative disorder of the juvenile myelomonocytic leukemia (JMML; 607785) type. The mutation was present in the patient's buccal cells but was absent in parental DNA. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis.

Kratz et al. (2009) identified a de novo heterozygous T58I mutation in a patient with Noonan syndrome who also had craniosynostosis, suggesting a genotype/phenotype correlation. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure.


.0012 NOONAN SYNDROME 3

KRAS, VAL14ILE
  
RCV000013420...

In 3 unrelated patients with Noonan syndrome-3 (NS3; 609942), Schubbert et al. (2006) identified a heterozygous 40G-A transition in the KRAS2 gene, resulting in a val14-to-ile (V14I) substitution. Each individual showed a mild clinical phenotype, and none had a history of myeloproliferative disorder or cancer. The patients were from a group of Noonan syndrome patients studied who did not have mutation in the PTPN11 gene (176876)


.0013 CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, PRO34ARG
  
RCV000043674...

In a 13-year-old female with the diagnosis of cardiofaciocutaneous syndrome (CFC2; 615278), Schubbert et al. (2006) found a heterozygous pro34-to-arg (P34R) mutation in the KRAS2 gene. The patient had pulmonic stenosis, left ventricular hypertrophy, Noonan-like facial features, short stature, short neck, broad thorax, lymphedema, chylothorax, left ptosis, severe developmental delay, and agenesis of the corpus callosum.


.0014 NOONAN SYNDROME 3

KRAS, VAL152GLY
  
RCV000013422

In a 1-year-old girl with the diagnosis of Noonan syndrome-3 (NS3; 609942), Carta et al. (2006) identified a 455T-G transversion in the KRAS2 gene, resulting in a val152-to-gly (V152G) substitution. The patient had macrocephaly with high and broad forehead, curly and sparse hair, hypertelorism, strabismus, epicanthic folds, downslanting palpebral fissures, hypoplastic nasal bridge with bulbous tip of the nose, high palate and macroglossia, low-set and posteriorly rotated ears, short neck with redundant skin, wide-set nipples, and umbilical hernia. She had been born at 32 weeks' gestation by cesarean section after a pregnancy complicated by a cystic hygroma detected at 12 weeks and polyhydramnios at 30 weeks. At birth she showed edema of the lower limbs. The phenotype showed features overlapping Costello syndrome (218040) (polyhydramnios, neonatal macrosomia, and macrocephaly, loose skin, and severe failure to thrive) and, to a lesser extent, CFC syndrome (615278) (macrocephaly and sparse hair).


.0015 NOONAN SYNDROME 3

KRAS, ASP153VAL
   RCV000013417...

In a 14-year-old girl with Noonan syndrome-3 (NS3; 609942) and some features of CFC syndrome (615278), Carta et al. (2006) identified a 458A-T transversion in the KRAS2 gene, resulting in an asp153-to-val (D153V) substitution. The girl had short stature and growth retardation and delayed bone age, cardiac defects (moderate ventricular hypertrophy, mild pulmonic stenosis, and atrial septal defect), dysmorphic features (hypertelorism, downslanting palpebral fissures, strabismus, low-set and thick ears, relative macrocephaly with high forehead, and a depressed nasal bridge), short and mildly webbed neck, wide-set nipples, and developmental delay. There was hyperpigmentation of the skin and a large cafe-au-lait spot on the face. Gestation was complicated by polyhydramnios.


.0016 PILOCYTIC ASTROCYTOMA, SOMATIC

KRAS, GLY13ARG
  
RCV000013424...

In 1 of 21 sporadic pilocytic astrocytoma (PA) (see 137800) samples, Sharma et al. (2005) identified a G-to-C transversion in the KRAS2 gene, resulting in a gly13-to-arg (G13R) substitution. The tumor arose in the cortex of an 11-year-old boy; the mutation was not identified in the germline of the patient. Immunohistochemical studies showed increased phospho-AKT (see 164730) activity compared to controls in all 21 PA samples, indicating increased activation of the Ras pathway. No mutations in the KRAS gene were observed in the other tumors, and none of the 21 tumors showed mutations in the HRAS (190020) or NRAS (164790) genes. Of note, the G13R substitution occurs in the same codon as another KRAS mutation (G13D; 190070.0003) identified in a breast carcinoma cell line.


.0017 CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, LYS5ASN
  
RCV000013425...

In a 7.5-month-old male infant with a clinical diagnosis of Costello syndrome (218040), Zenker et al. (2007) identified a heterozygous 15A-T transversion in exon 1 of the KRAS2 gene, resulting in a lys5-to-asn (K5N) substitution. The patient had hypertelorism, downslanting palpebral fissures, coarse facies, pectus carinatum, sparse hair, redundant skin, and moderate mental retardation. Zenker et al. (2007) noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; 615278), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020).


.0018 CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, PHE156LEU
  
RCV000013426...

In a male infant with a clinical diagnosis of Costello syndrome (218040) who died suddenly at age 14 months, Zenker et al. (2007) identified a heterozygous 468C-G transversion in the KRAS2 gene, resulting in a phe156-to-leu (F156L) substitution. The patient had coarse facies, cardiac defects, sparse hair, loose and redundant skin, developmental delay, and moderate mental retardation. Zenker et al. (2007) noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; 615278), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020).


.0019 NOONAN SYNDROME 3

KRAS, LYS5GLU
  
RCV000013427...

In a 20-year-old woman with clinical features typical of Costello syndrome (218040) and additional findings seen in Noonan syndrome (NS3; 609942), Bertola et al. (2007) identified a 194A-G transition in exon 2 of the KRAS gene, resulting in a lys5-to-glu (K5E) substitution. The mutation was not found in her unaffected mother or brother or in 100 controls.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020).

Bertola et al. (2012) reported a patient with a germline K5E mutation and dysmorphic features who developed multiple diffuse schwannomas.


.0020 NOONAN SYNDROME 3

KRAS, GLY60SER
  
RCV000013428...

In a patient with Noonan syndrome-3 (NS3; 609942) and craniosynostosis, Kratz et al. (2009) identified a de novo heterozygous 178G-A transition in the KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure.

A mutation in this same codon (G60R; 190070.0009) has been found in a patient with cardiofaciocutaneous syndrome (CFC2; 615278).


.0021 CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, TYR71HIS
  
RCV000024617

In a mother and son with variable features of cardiofaciocutaneous syndrome (CFC2; 615278), Stark et al. (2012) identified a heterozygous 211T-C transition in exon 3 of the KRAS gene, resulting in a tyr71-to-his (Y71H) substitution in a highly conserved residue close to a region that is important for effector and regulator binding. The mutation was not found in 500 control individuals and was shown by in vitro studies to increase effector affinity. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse. She had attended a school for children with special needs. Both patients showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 (601097) testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The authors stated that this was the first documented vertically transmitted KRAS mutation.

Y71 is located at the end of the switch II region of KRAS. Using in vitro assays and transfected COS-7 cells, Cirstea et al. (2013) found that the Y71H mutation increased the binding affinity of KRAS for its major effector, RAF1 kinase (164760), leading to increased activation of MEK1 (176872)/MEK2 (601263) and ERK1 (601795)/ERK2 (176948), irrespective of stimulation. The mutation did not alter the rate of nucleotide dissociation by KRAS.


.0022 CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, LYS147GLU
  
RCV000024618...

In a girl with variable features of cardiofaciocutaneous syndrome (CFC2; 615278), Stark et al. (2012) identified a de novo heterozygous 439A-G transition in exon 4 of the KRAS gene, resulting in a lys147-to-glu (K147E) substitution in a highly conserved residue close to known mutations. Lys147 is part of a motif involved in the binding network for guanine nucleotides, which determine the activation state of RAS proteins. In vitro studies demonstrated that the K147E mutant protein predominates in the active GTP-bound form, probably due to facilitated uncatalyzed GDP/GTP exchange. The patient was 1 of a female dizygotic twin pair; the other twin was unaffected. The patient had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome. Reexamination at age 3.5 years showed coarser facial features more consistent with CFC. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development.

K147 is a conserved amino acid within a motif required for guanine base binding by KRAS. K147 is also ubiquitinated, leading to increased KRAS activation by GEF proteins. Using in vitro assays and transfected COS-7 cells, Cirstea et al. (2013) found that the K147E mutation significantly increased nucleotide dissociation in KRAS, generating a self-activating protein that acted independently of upstream signaling. However, overactivity of K147E mutant KRAS was subject to normal downregulation by RasGAP (see 139150) and had 2-fold lower affinity for RAF1 kinase (164760).


.0023 RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC

KRAS, GLY13CYS
  
RCV000038268...

In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous c.37G-T transversion in the KRAS gene, resulting in a gly13-to-cys (G13C) substitution. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function.


.0024 OCULOECTODERMAL SYNDROME, SOMATIC

KRAS, LEU19PHE
  
RCV000201922...

In a 25-year-old man with oculoectodermal syndrome (OES; 600268), who was one of the original boys (patient 2) with OES described by Toriello et al. (1993), Peacock et al. (2015) identified heterozygosity for a somatic c.57G-C transversion (c.57G-C, NM_033360.3) in the KRAS gene, resulting in a leu19-to-phe (L19F) substitution (allelic frequency, 16.9%). The mutation was also found in samples from the patient's skin, bone marrow from proximal femur, and peripheral blood (allelic frequencies, 4.7-10.3%).


.0025 ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC

KRAS, GLY12ASP
   RCV000013411...

Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant (190070.0026) were present in 2.4 to 4.0% of the sequence reads per sample. The G12D mutation drove MAPK-ERK activity in endothelial cells.


.0026 ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC

KRAS, GLY12VAL
   RCV000013413...

Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-val (G12D, c.35G-T) mutation in a total of 13 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12D variant (190070.0025) were present in 2.4 to 4.0% of the sequence reads per sample. The G12V mutation drove MAPK-ERK activity in endothelial cells.


.0027 OCULOECTODERMAL SYNDROME, SOMATIC

KRAS, ALA146THR
  
RCV000178223...

In lesional tissues from a 6-year-old boy with oculoectodermal syndrome (OES; 600268), originally reported by Aslan et al. (2014), Boppudi et al. (2016) identified somatic mosaicism for a c.436G-A transition (c.436G-A, ENST00000311936) in the KRAS gene, resulting in an ala146-to-thr (A146T) substitution. The mutant allele frequency ranged from 11% to 38% in lesional tissue samples, and was not found in leukocyte DNA.

In a 4-year-old Mexican girl with OES (patient 1), Chacon-Camacho et al. (2019) identified somatic mosaicism for the A146T mutation in the KRAS gene. The mutant allele frequency was 28% in lesional tissue, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells.


.0028 OCULOECTODERMAL SYNDROME, SOMATIC

KRAS, ALA146VAL
  
RCV000423608...

In 2 unrelated children with oculoectodermal syndrome (OES; 600268), Boppudi et al. (2016) identified somatic mosaicism for a c.437C-T transition (c.437C-T, ENST00000311936) in the KRAS gene, resulting in an ala146-to-val (A146V) substitution. The mutant allele frequency ranged from less than 10% to 40% in lesional tissue samples, and was not found in leukocyte DNA.

In a 12-year-old Mexican boy with OES (patient 2), Chacon-Camacho et al. (2019) identified somatic mosaicism for the A146V mutation in the KRAS gene. The mutant allele frequency was 26% to 27% in lesional tissues, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells.


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Sonja A. Rasmussen - updated : 07/25/2022
Bao Lige - updated : 03/09/2022
Ada Hamosh - updated : 05/13/2020
Ada Hamosh - updated : 12/10/2019
Ada Hamosh - updated : 09/12/2019
Marla J. F. O'Neill - updated : 08/01/2019
Ada Hamosh - updated : 03/06/2018
Ada Hamosh - updated : 09/30/2016
Ada Hamosh - updated : 02/17/2016
Nara Sobreira - updated : 11/11/2015
Cassandra L. Kniffin - updated : 11/12/2014
Patricia A. Hartz - updated : 5/23/2014
Ada Hamosh - updated : 12/6/2013
Ada Hamosh - updated : 7/9/2013
Ada Hamosh - updated : 7/8/2013
Cassandra L. Kniffin - updated : 1/30/2013
Cassandra L. Kniffin - updated : 7/25/2012
Ada Hamosh - updated : 7/17/2012
Cassandra L. Kniffin - updated : 6/28/2012
Marla J. F. O'Neill - updated : 11/29/2011
Cassandra L. Kniffin - updated : 2/21/2011
Ada Hamosh - updated : 2/3/2011
Ada Hamosh - updated : 8/17/2010
Ada Hamosh - updated : 3/9/2010
Ada Hamosh - updated : 12/29/2009
Cassandra L. Kniffin - updated : 10/27/2009
Ada Hamosh - updated : 10/13/2009
Marla J. F. O'Neill - updated : 6/1/2009
Cassandra L. Kniffin - updated : 3/3/2009
Ada Hamosh - updated : 1/20/2009
Ada Hamosh - updated : 7/29/2008
Cassandra L. Kniffin - updated : 3/17/2008
Ada Hamosh - updated : 11/12/2007
George E. Tiller - updated : 4/5/2007
Cassandra L. Kniffin - reorganized : 3/8/2007
Cassandra L. Kniffin - updated : 3/2/2007
Cassandra L. Kniffin - updated : 2/15/2007
Ada Hamosh - updated : 2/8/2007
Ada Hamosh - updated : 11/28/2006
Victor A. McKusick - updated : 6/13/2006
Patricia A. Hartz - updated : 4/10/2006
Patricia A. Hartz - updated : 3/28/2006
Victor A. McKusick - updated : 2/24/2006
Ada Hamosh - updated : 9/7/2005
Stylianos E. Antonarakis - updated : 3/28/2005
Marla J. F. O'Neill - updated : 3/22/2005
Victor A. McKusick - updated : 12/16/2003
John A. Phillips, III - updated : 9/2/2003
John A. Phillips, III - updated : 9/2/2003
Ada Hamosh - updated : 9/17/2002
Victor A. McKusick - updated : 8/15/2002
Victor A. McKusick - updated : 12/13/2001
Victor A. McKusick - updated : 9/26/2001
Victor A. McKusick - updated : 9/4/2001
Victor A. McKusick - updated : 8/24/2001
Ada Hamosh - updated : 4/23/2001
Ada Hamosh - updated : 4/28/2000
Ada Hamosh - updated : 2/11/2000
Paul Brennan - updated : 7/31/1998
Victor A. McKusick - updated : 3/27/1998
Paul Brennan - updated : 11/14/1997
Victor A. McKusick - edited : 3/3/1997
Mark H. Paalman - edited : 1/10/1997
Creation Date:
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alopez : 08/01/2019
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alopez : 8/31/2015
carol : 11/18/2014
mcolton : 11/13/2014
ckniffin : 11/12/2014
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mgross : 5/23/2014
mcolton : 5/22/2014
mcolton : 5/22/2014
alopez : 12/6/2013
alopez : 7/9/2013
alopez : 7/9/2013
alopez : 7/8/2013
alopez : 6/20/2013
alopez : 2/6/2013
ckniffin : 1/30/2013
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carol : 7/26/2012
carol : 7/25/2012
ckniffin : 7/25/2012
alopez : 7/19/2012
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alopez : 3/7/2012
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ckniffin : 2/21/2011
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alopez : 8/20/2010
terry : 8/17/2010
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terry : 12/29/2009
carol : 11/23/2009
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ckniffin : 10/27/2009
alopez : 10/23/2009
terry : 10/13/2009
joanna : 9/14/2009
wwang : 6/3/2009
terry : 6/1/2009
wwang : 3/5/2009
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alopez : 2/6/2009
carol : 2/6/2009
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terry : 7/29/2008
wwang : 3/19/2008
ckniffin : 3/17/2008
alopez : 11/14/2007
alopez : 11/14/2007
terry : 11/12/2007
carol : 9/10/2007
carol : 9/6/2007
alopez : 4/13/2007
terry : 4/5/2007
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carol : 3/8/2007
ckniffin : 3/8/2007
ckniffin : 3/2/2007
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alopez : 2/8/2007
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mgross : 4/14/2006
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alopez : 11/17/1997
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mark : 3/3/1997
mark : 1/10/1997
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terry : 11/6/1996
terry : 10/31/1996
mark : 8/10/1995
mimadm : 6/7/1995
carol : 11/1/1993
carol : 6/30/1993
carol : 6/22/1993
carol : 6/7/1993

* 190070

KRAS PROTOONCOGENE, GTPase; KRAS


Alternative titles; symbols

V-KI-RAS2 KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG
ONCOGENE KRAS2; KRAS2
KIRSTEN MURINE SARCOMA VIRUS 2; RASK2
C-KRAS


Other entities represented in this entry:

V-KI-RAS1 PSEUDOGENE, INCLUDED; KRAS1P, INCLUDED
ONCOGENE KRAS1, INCLUDED; KRAS1, INCLUDED
KIRSTEN RAS1, INCLUDED; RASK1, INCLUDED

HGNC Approved Gene Symbol: KRAS

Cytogenetic location: 12p12.1     Genomic coordinates (GRCh38): 12:25,205,246-25,250,929 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12p12.1 Arteriovenous malformation of the brain, somatic 108010 3
Bladder cancer, somatic 109800 3
Breast cancer, somatic 114480 3
Cardiofaciocutaneous syndrome 2 615278 Autosomal dominant 3
Gastric cancer, somatic 613659 3
Leukemia, acute myeloid, somatic 601626 3
Lung cancer, somatic 211980 3
Noonan syndrome 3 609942 Autosomal dominant 3
Oculoectodermal syndrome, somatic 600268 3
Pancreatic carcinoma, somatic 260350 3
RAS-associated autoimmune leukoproliferative disorder 614470 Autosomal dominant 3
Schimmelpenning-Feuerstein-Mims syndrome, somatic mosaic 163200 3

TEXT

Description

The KRAS gene encodes the human cellular homolog of a transforming gene isolated from the Kirsten rat sarcoma virus. The RAS proteins are GDP/GTP-binding proteins that act as intracellular signal transducers. The most well-studied members of the RAS (derived from 'RAt Sarcoma' virus) gene family include KRAS, HRAS (190020), and NRAS (164790). These genes encode immunologically related proteins with a molecular mass of 21 kD and are homologs of rodent sarcoma virus genes that have transforming abilities. While these wildtype cellular proteins in humans play a vital role in normal tissue signaling, including proliferation, differentiation, and senescence, mutated genes are potent oncogenes that play a role in many human cancers (Weinberg, 1982; Kranenburg, 2005).


Cloning and Expression

Der et al. (1982) identified a new human DNA sequence homologous to the transforming oncogene of the Kirsten (ras-K) murine sarcoma virus within mouse 3T3 fibroblast cells transformed by DNA from an undifferentiated human lung cancer cell line (LX-1). The findings showed that KRAS could act as an oncogene in human cancer.

Chang et al. (1982) isolated clones corresponding to the human cellular KRAS gene from human placental and embryonic cDNA libraries. Two isoforms were identified, designated KRAS1 and KRAS2. KRAS1 contained 0.9 kb homologous to viral Kras and had 1 intervening sequence, and KRAS2 contained 0.3 kb homologous to viral Kras. McCoy et al. (1983) characterized the KRAS gene isolated from a human colon adenocarcinoma cell line (SW840) and determined that it corresponded to KRAS2 as identified by Chang et al. (1982). The KRAS2 oncogene was amplified in several tumor cell lines.

McGrath et al. (1983) cloned the KRAS1 and KRAS2 genes and determined that the KRAS1 gene is a pseudogene. The KRAS2 gene encodes a 188-residue protein with a molecular mass of 21.66 kD. It showed only 6 amino acid differences from the viral gene. Comparison of the 2 KRAS genes showed that KRAS1 is lacking several intervening sequences, consistent with it being a pseudogene derived from a processed KRAS2 mRNA. The major KRAS2 mRNA transcript is 5.5 kb. Alternative splicing results in 2 variants, isoforms A and B, that differ in the C-terminal region.

Alternative splicing of exon 5 results in the KRASA and KRASB isoforms. Exon 6 contains the C-terminal region in KRASB, whereas it encodes the 3-prime untranslated region in KRASA. The differing C-terminal regions of these isoforms are subjected to posttranslational modifications. The differential posttranslational processing has profound functional effects leading to alternative trafficking pathways and protein localization (Carta et al., 2006).

Tsai et al. (2015) noted that the use of alternative fourth exons generates 2 KRAS variants, KRAS4A and KRAS4B, the produce isoforms with distinct membrane-targeting sequences. Using confocal microscopy, Tsai et al. (2015) showed that GFP-tagged KRAS4A localized exclusively to the plasma membrane (PM) of HEK293 cells. Palmitoylation of cys180 in the hypervariable region of KRAS4A was required for efficient targeting of KRAS4A to the PM, but a second signal could target KRAS4A to the PM in the absence of cys180 palmitoylation. The authors identified a C-terminal polybasic region in KRAS4A with 2 clusters of positively charged residues (PB1 and PB2). They found that both palmitoylation and PB2 were required for efficient targeting of KRAS4A to the PM. RT-PCR analysis showed that KRAS4A was expressed in all human cancer cell lines examined, especially in colorectal carcinoma and melanoma cell lines.


Gene Structure

McGrath et al. (1983) first reported that the KRAS2 gene spans 38 kb and contains 4 exons. Detailed sequence analysis showed that exon 4 has 2 forms, which the authors designated 4A and 4B.

The KRAS2 gene has been shown to have a total of 6 exons. Exons 2, 3, and 4 are invariant coding exons, whereas exon 5 undergoes alternative splicing. KRASB results from exon 5 skipping. In KRASA mRNA, exon 6 encodes the 3-prime untranslated region. In KRASB mRNA, exon 6 encodes the C-terminal region (Carta et al., 2006).


Mapping

By in situ hybridization, Popescu et al. (1985) mapped the KRAS2 gene to chromosome 12p12.1-p11.1. By linkage with RFLPs, O'Connell et al. (1985) confirmed the approximate location of KRAS2 on 12p12.1.

Pseudogene

The KRAS1 gene is a KRAS2 pseudogene and has been assigned to chromosome 6 (O'Brien et al., 1983; McBride et al., 1983). By in situ hybridization, Popescu et al. (1985) assigned the KRAS1 gene to 6p12-p11. Because KRAS1 was found to be a pseudogene, its official symbol was changed to KRAS1P.


Gene Function

Johnson et al. (2005) found that the 3 human RAS genes, HRAS, KRAS, and NRAS, contain multiple let-7 (605386) complementary sites in their 3-prime UTRs that allow let-7 miRNA to regulate their expression. Let-7 expression was lower in lung tumors than in normal lung tissue, whereas expression of the RAS proteins was significantly higher in lung tumors, suggesting a possible mechanism for let-7 in cancer.

Bivona et al. (2006) found that the subcellular localization and function of Kras in mammalian cells was modulated by Pkc (see 176960). Phosphorylation of Kras by Pkc agonists induced rapid translocation of Kras from the plasma membrane to several intracellular membranes, including the outer mitochondrial membrane, where Kras associated with Bclxl (BCL2L1; 600039). Phosphorylated Kras required Bclxl for induction of apoptosis.

Yeung et al. (2006) devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the change of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as KRAS, RAC1 (602048), and c-SRC (190090) that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis.

Heo et al. (2006) surveyed plasma membrane targeting mechanisms by imaging the subcellular localization of 125 fluorescent protein-conjugated Ras, Rab, Arf, and Rho proteins. Of 48 proteins that were localized to the plasma membrane, 37 contained clusters of positively charged amino acids. To test whether these polybasic clusters bind negatively charged phosphatidylinositol 4,5-bisphosphate lipids, Heo et al. (2006) developed a chemical phosphatase activation method to deplete plasma membrane phosphatidylinositol 4,5-bisphosphate. Unexpectedly, proteins with polybasic clusters dissociated from the plasma membrane only when both phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate were depleted, arguing that both lipid second messengers jointly regulate plasma membrane targeting.

Gazin et al. (2007) performed a genomewide RNA interference (RNAi) screen in KRAS-transformed NIH 3T3 cells and identified 28 genes required for RAS-mediated epigenetic silencing of the proapoptotic FAS gene (TNFRSF6; 134637). At least 9 of these RAS epigenetic silencing effectors (RESEs), including the DNA methyltransferase DNMT1 (126375), were directly associated with specific regions of the FAS promoter in KRAS-transformed NIH 3T3 cells but not in untransformed NIH 3T3 cells. RNAi-mediated knockdown of any of the 28 RESEs resulted in failure to recruit DNMT1 to the FAS promoter, loss of FAS promoter hypermethylation, and derepression of FAS expression. Analysis of 5 other epigenetically repressed genes indicated that RAS directs the silencing of multiple unrelated genes through a largely common pathway. Finally, Gazin et al. (2007) showed that 9 RESEs are required for anchorage-independent growth and tumorigenicity of KRAS-transformed NIH 3T3 cells; these 9 genes had not previously been implicated in transformation by RAS. Gazin et al. (2007) concluded that RAS-mediated epigenetic silencing occurs through a specific, complex pathway involving components that are required for maintenance of a fully transformed phenotype.

Haigis et al. (2008) used genetically engineered mice to determine whether and how the related oncogenes Kras and Nras (164790) regulate homeostasis and tumorigenesis in the colon. Expression of Kras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek (see 176872)-dependent manner. Nras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc (611731)-mutant colonic tumor, activation of Kras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This Kras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant Kras were hypersensitive to inhibition of Raf (see 164760) but not Mek. Haigis et al. (2008) concluded that their studies demonstrated clear phenotypic differences between mutant Kras and Nras, and suggested that the oncogenic phenotype of mutant Kras might be mediated by noncanonical signaling through Ras effector pathways.

By studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF (164757) genes, Yun et al. (2009) found that GLUT1 (138140), encoding glucose transporter-1, was 1 of 3 genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low-glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wildtype KRAS alleles were subjected to a low-glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired KRAS mutations not present in their parents. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Yun et al. (2009) concluded that, taken together, these data suggested that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors.

Meylan et al. (2009) showed that the NF-kappa-B (see 164011) pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (191170) and expression of oncogenic Kras containing the G12D mutation resulted in NF-kappa-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappa-B inhibition. Furthermore, the inhibition of NF-kappa-B signaling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or after tumor progression, resulted in significantly reduced tumor development. Meylan et al. (2009) concluded that, together, their results indicated a critical function for NF-kappa-B signaling in lung tumor development and, further, that this requirement depends on p53 status.

Barbie et al. (2009) used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the noncanonical I-kappa-B kinase TBK1 (604834) was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappa-B antiapoptotic signals involving c-REL (164910) and BCLXL (BCL2L1; 600039) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. Barbie et al. (2009) concluded that TBK1 and NF-kappa-B signaling are essential in KRAS mutant tumors, and establish a general approach for the rational identification of codependent pathways in cancer.

In Drosophila eye-antennal discs, cooperation between Ras(V12), an oncogenic form of the Ras85D protein, and loss-of-function mutations in the conserved tumor suppressor 'scribble' (607733) gives rise to metastatic tumors that display many characteristics observed in human cancers (summary by Wu et al., 2010). Wu et al. (2010) showed that clones of cells bearing different mutations can cooperate to promote tumor growth and invasion in Drosophila. The authors found that the Ras(V12) and scrib-null mutations can also cause tumors when they affect different adjacent epithelial cells. Wu et al. (2010) showed that this interaction between Ras(V12) and scrib-null clones involves JNK signaling propagation and JNK-induced upregulation of JAK/STAT-activating cytokines (see 604260), a compensatory growth mechanism for tissue homeostasis. The development of Ras(V12) tumors can also be triggered by tissue damage, a stress condition that activates JNK signaling. The authors suggested that similar cooperative mechanisms could have a role in the development of human cancers.

Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDE-delta (PDED; 602676), which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm (Chandra et al., 2012; Zhang et al., 2004). Zimmermann et al. (2013) reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS.

Yun et al. (2015) found that cultured human colorectal cancer cells harboring KRAS or BRAF (164757) mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 (138140) glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wildtype cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. Yun et al. (2015) suggested that their results provided a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.

Using coexpression analysis, Tsai et al. (2015) showed that, unlike KRAS4B, KRAS4A did not bind PDE6-delta, even though KRAS4A and KRAS4B had identical steady-state localizations at the PM. Further analysis revealed that both membrane-targeting signals of KRAS4A supported its downstream signaling, and that either of the 2 was sufficient for signal output.

Yao et al. (2019) developed an unbiased functional target discovery platform to query oncogeneic KRAS-dependent changes of the pancreatic ductal adenocarcinoma surfaceome, which revealed syndecan-1 (SDC1; 186355) as a protein that is upregulated at the cell surface by oncogenic KRAS. Localization of SDC1 at the cell surface, where it regulates macropinocytosis, an essential metabolic pathway that fuels pancreatic ductal adenocarcinoma cell growth, is essential for disease maintenance and progression.

Amendola et al. (2019) reported a direct, GTP-dependent interaction between the KRAS exon 4A-specific isoform KRAS4A and hexokinase-1 (HK1; 142600) that alters the activity of the kinase, and thereby established that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.

Regulation of KRAS Expression by KRAS1P Transcript Levels

Following their finding that PTENP1 (613531), a pseudogene of the PTEN (601728) tumor suppressor gene, can derepress PTEN by acting as a decoy for PTEN-targeting miRNAS, Poliseno et al. (2010) extended their analysis to the oncogene KRAS and its pseudogene KRAS1. KRAS1P 3-prime UTR overexpression in DU145 prostate cancer cells resulted in increased KRAS mRNA abundance and accelerated cell growth. They also found that KRAS and KRAS1P transcript levels were positively correlated in prostate cancer. Notably, the KRAS1P locus 6p12-p11 is amplified in different human tumors, including neuroblastoma, retinoblastoma, and hepatocellular carcinoma. Poliseno et al. (2010) concluded that their findings together pointed to a putative protooncogenic role for KRAS1P, and supported the notion that pseudogene functions mirror the functions of their cognate genes as explained by a miRNA decoy mechanism.


Molecular Genetics

Role in Solid Tumors

KRAS is said to be one of the most activated oncogenes, with 17 to 25% of all human tumors harboring an activating KRAS mutation (Kranenburg, 2005). Critical regions of the KRAS gene for oncogenic activation include codons 12, 13, 59, 61, and 63 (Grimmond et al., 1992). These activating mutations cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase activating proteins (Zenker et al., 2007).

In a study of 96 human tumors or tumor cell lines in the NIH 3T3 transforming system, Pulciani et al. (1982) found a mutated HRAS locus only in a single cancer cell line, whereas transforming KRAS genes were identified in 8 different carcinomas and sarcomas. KRAS appeared to be involved in malignancy much more often than HRAS. In a serous cystadenocarcinoma of the ovary (167000), Feig et al. (1984) showed the presence of an activated KRAS oncogene that was not activated in normal cells of the same patient. The transforming gene product displayed an electrophoretic mobility pattern that differed from that of KRAS transforming proteins in other tumors, suggesting a novel somatic KRAS mutation in this tumor.

In a cell line of human lung cancer (211980), Nakano et al. (1984) identified a mutation in the KRAS2 gene (190070.0001), resulting in gene activation with transforming ability of the mutant protein.

Rodenhuis et al. (1987) used a novel, highly sensitive assay based on oligonucleotide hybridization following in vitro amplification to examine DNA from 39 lung tumor specimens. The KRAS gene was found to be activated by point mutations in codon 12 in 5 of 10 adenocarcinomas. Two of these tumors were less than 2 cm in size and had not metastasized. No HRAS, KRAS, or NRAS mutations were observed in 15 squamous cell carcinomas, 10 large cell carcinomas, 1 carcinoid tumor, 2 metastatic adenocarcinomas from primary tumors outside the lung, and 1 small cell carcinoma. An approximately 20-fold amplification of the unmutated KRAS gene was observed in a tumor that proved to be a solitary lung metastasis of a rectal carcinoma.

Yanez et al. (1987) found mutations in codon 12 of the KRAS gene in 4 of 16 colon cancers (114500), 2 of 27 lung cancers, and 1 of 8 breast cancers (114480); no mutations were found at codon position 61.

The highest observed frequency of KRAS2 point mutations occurs in pancreatic carcinomas (260350), with 90% of the patients having at least 1 KRAS2 mutation (Almoguera et al., 1988; Smit et al., 1988). Most of these mutations are in codon 12 (see, e.g., G12D, 190070.0005 and G12V, 190070.0006) (Hruban et al., 1993).

Burmer and Loeb (1989) identified KRAS2 mutations in both diploid and aneuploid cells in colon adenomas and carcinomas. Twenty-six of 40 colon carcinomas contained mutations at codon 12, and 9 of the 12 adenomas studied contained similar mutations.

Sidransky et al. (1992) found that KRAS mutations were detectable in DNA purified from stool in 8 of 9 patients with colorectal tumors that contained KRAS mutations. Takeda et al. (1993) used a mutant-allele-specific amplification (MASA) method to detect KRAS mutations in cells obtained from the sputum of patients with lung cancer. A mutation was found in 1 of 5 patients studied. The authors suggested that the MASA system could be applied to an examination of metastatic lung carcinomas, particularly from adenocarcinomas of the colon and pancreas in which KRAS mutations are frequently detected, and to mass screening for colorectal tumors, using DNA isolated from feces as a template.

Lee et al. (1995) identified mutations in codon 12 of the KRAS gene in 11 (7.9%) of 140 gastric cancers (613659). Seven cases had a G12S mutation (190070.0007) and 2 had a G12D mutation (190070.0005). Tumors located in the upper third of the stomach had a significantly higher frequency of KRAS codon 12 mutations (3 of 8; 37.5%) compared with tumors located in the middle (4 of 29; 13.8%) or lower (3 of 99; 3%) thirds of the stomach (P = 0.001). Among 8 patients with stomach cancer located in the upper part of the stomach, death occurred in 4 of 5 patients with tumors without KRAS gene mutations, but in none of the 3 patients with KRAS gene-mutated tumors.

Otori et al. (1997) examined tissue sections from 19 hyperplastic colorectal polyps for mutations in exons 12 and 13 of the KRAS gene. KRAS mutations were detected in 9 (47%) of 19 polyps, suggesting that some hyperplastic colorectal polyps may be true premalignant lesions.

KRAS activation has been recognized in microdissected foci of pancreatic intraepithelial neoplasia (Cubilla and Fitzgerald, 1976; Hruban et al., 2000; Hruban et al., 2000), the candidate precursor lesion of pancreatic cancer previously known as ductal cell hyperplasia. Laghi et al. (2002) found that KRAS codon 12 was mutated in 34 of 41 (83%) pancreatic cancers and in 11 of 13 (85%) biliary cancers. Multiple distinct KRAS mutations were found in 16 pancreatic cancers and in 8 biliary cancers. Multiple KRAS mutations were more frequent in cancers with detectable pancreatic intraepithelial neoplasia than in those without, and individual precursor lesions of the same neoplastic pancreas harbored distinct mutations. The results indicated that clonally distinct precursor lesions of pancreatic cancer may variably contribute to tumor development.

Nikiforova et al. (2003) analyzed a series of 88 conventional follicular (188470) and Hurthle cell (607464) thyroid tumors for HRAS, NRAS, or KRAS mutations and PAX8 (167415)-PPARG (601487) rearrangements. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARG rearrangement, and only 1 (3%) had both. Of follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARG rearrangement, and 48% had neither. Hurthle cell tumors infrequently had PAX8-PPARG rearrangement or RAS mutations.

Rajagopalan et al. (2002) systematically evaluated mutations in the BRAF (164757) and KRAS genes in 330 colorectal tumors. There were 32 mutations in BRAF and 169 mutations in KRAS; no tumor exhibited mutations in both BRAF and KRAS. Rajagopalan et al. (2002) concluded that BRAF and KRAS mutations are equivalent in their tumorigenic effects and are mutated at a similar phase of tumorigenesis, after initiation but before malignant conversion. Kim et al. (2003) found 7 KRAS missense mutations in 66 gastric cancers and 16 gastric cancer cell lines. No BRAF mutations were found.

Oliveira et al. (2004) investigated KRAS in 158 hereditary nonpolyposis colorectal cancer (HNPCC2; 609310) tumors from patients with germline MLH1 (120436), MSH2 (609309) or MSH6 (600678) mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H colorectal cancers were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D (190070.0003) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02) or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. The authors concluded that depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status) and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway.

Sommerer et al. (2005) analyzed the KRAS gene in 30 seminomas and 32 nonseminomatous GCTs (see 273300) with a mixture of embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mature teratoma. KRAS mutations, all involving codon 12, were identified in 2 (7%) of 30 seminomas and 3 (9%) of 32 nonseminomas.

Groesser et al. (2012) identified somatic mutations in the KRAS gene (G12D, 190070.0005 and G12V, 190070.0006) in 3 (5%) of 65 nevus sebaceous tumors (see 162900). The G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200). The authors postulated that the mosaic mutation likely extends to extracutaneous tissues in the latter disorder, which could explain the phenotypic pleiotropy.

Vermeulen et al. (2013) quantified the competitive advantage in tumor development of Apc (611731) loss, Kras activation, and p53 (191170) mutations in the mouse intestine. Their findings indicated that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wildtype stem cells after biased but still stochastic events. Furthermore, Vermeulen et al. (2013) found that p53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene were favored. Vermeulen et al. (2013) concluded that their work confirmed the notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.

Hematologic Malignancies

The myelodysplastic syndrome is a preleukemic hematologic disorder characterized by low blood counts, bone marrow cells of abnormal appearance, and progression to acute leukemia in as many as 30% of patients. Liu et al. (1987) identified a transforming allele in the KRAS gene in 2 of 4 patients with preleukemia and in 1 who progressed to acute leukemia from myelodysplastic syndrome. In 1 preleukemic patient, they detected a novel mutation in codon 13 of KRAS in bone marrow cells harvested 1.5 years before the acute leukemia developed. The findings provided evidence that RAS mutations may be involved in the early stages of human leukemia.

In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; 601626), Bollag et al. (1996) identified a somatic in-frame 3-bp insertion in the KRAS gene (190070.0008).

Bezieau et al. (2001) used ARMS (allele-specific amplification method) to evaluate the incidence of NRAS- and KRAS2-activating mutations in patients with multiple myeloma (254500) and related disorders. Mutations were more frequent in KRAS2 than in NRAS. The authors concluded that early mutations in these 2 oncogenes may play a major role in the oncogenesis of multiple myeloma and primary plasma cell leukemia.

In white blood cells derived from 3 unrelated girls with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, 190070.0003; G12D, 190070.0005; and G12S, 190070.0007). The patients were ascertained from a cohort of 80 children with JMML.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the NRAS (164790) or KRAS genes in 23/200 (12%) samples.

RAS-Associated Autoimmune Leukoproliferative Disorder

In 2 unrelated girls with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified different somatic heterozygous gain-of-function mutations in the KRAS gene (G12D, 190070.0005 and G13C, 190070.0023). The patients presented in early childhood with lymphadenopathy, splenomegaly, and autoimmune disorders. One patient had recurrent infections. In vitro studies indicated that the activating KRAS mutations impaired cytokine withdrawal-induced T-cell apoptosis through suppression of the proapoptotic protein BIM (BCL2L11; 603827) and facilitated lymphocyte proliferation through downregulation of CDKN1B (600778).

Cardiofaciocutaneous Syndrome, Noonan Syndrome 3, and Costello Syndrome

Cardiofaciocutaneous (CFC) syndrome (see 115150) is characterized by distinctive facial appearance, heart defects, and mental retardation. CFC shows phenotypic overlap with Noonan syndrome (see 163950) and Costello syndrome (218040). Approximately 40% of individuals with clinically diagnosed Noonan syndrome have gain-of-function mutations in protein-tyrosine phosphatase SHP2 (PTPN11; 176876). Aoki et al. (2005) identified mutations in the HRAS gene in 12 of 13 individuals with Costello syndrome, suggesting that the activation of the RAS-MAPK pathway is the common underlying mechanism of Noonan syndrome, Costello syndrome, and possibly CFC syndrome. In 2 of 43 unrelated individuals with CFC syndrome (CFC2; 615278), Niihori et al. (2006) identified different heterozygous KRAS mutations (G60R, 190070.0009 and D153V, 190070.0010). Neither mutation had previously been identified in individuals with cancer. In the same study, Niihori et al. (2006) found 8 different mutations in the BRAF gene (164757), an isoform in the RAF protooncogene family, in 16 of 40 individuals with CFC syndrome.

Schubbert et al. (2006) identified 3 de novo germline KRAS mutations (190070.0010-190070.0012) in 5 individuals with Noonan syndrome-3 (NS3; 609942).

In 2 individuals exhibiting a severe Noonan syndrome-3 phenotype with features overlapping those of CFC and Costello syndromes, Carta et al. (2006) identified 2 different heterozygous KRAS mutations (190070.0014 and 190070.0015). Both mutations were de novo and affected exon 6, which encodes the C-terminal portion of KRAS isoform B but does not contribute to KRAS isoform A. Structural analysis indicated that both substitutions perturb the conformation of the guanine ring-binding pocket of the protein, predicting an increase in the guanine diphosphate/guanine triphosphate (GTP) dissociation rate that would favor GTP binding to the KRASB isoform and bypass the requirement for a guanine nucleotide exchange factor.

Zenker et al. (2007) identified 11 different germline mutations in the KRAS gene, including 8 novel mutations, in a total of 12 patients with a clinical diagnosis of CFC (2), Noonan syndrome-3 (7), CFC/Noonan syndrome overlap (1), or Costello syndrome (2). All patients showed mild to moderate mental retardation. The 2 unrelated infants with Costello syndrome had 2 different heterozygous mutations (190070.0017-190070.0018). Both patients had coarse facies, loose and redundant skin with deep palmar creases, heart defects, failure to thrive, and moderate mental retardation. Zenker et al. (2007) noted that these patients may later develop features of CFC syndrome, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these diverse but phenotypically related disorders.

In a 20-year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome, who was negative for mutations in the PTPN11 and HRAS genes, Bertola et al. (2007) identified a mutation in the KRAS gene (K5E; 190070.0019). The authors noted that this mutation was in the same codon as that of 1 of the patients reported by Zenker et al. (2007) (K5N; 190070.0017).

Schulz et al. (2008) identified mutations in the KRAS gene in 3 (5.9%) of 51 CFC patients.

Development of Resistance to Chemotherapeutic Agents

Misale et al. (2012) showed that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR (131550) treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. Misale et al. (2012) concluded that their results identified KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicated that the emergence of KRAS mutant clones can be detected noninvasively months before radiographic progression, and suggested early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance.

Diaz et al. (2012) determined whether mutant KRAS DNA could be detected in the circulation of 28 patients receiving monotherapy with panitumumab, a therapeutic anti-EGFR antibody. They found that 9 out of 24 (38%) patients whose tumors were initially KRAS wildtype developed detectable mutations in KRAS in their sera, 3 of which developed multiple different KRAS mutations. The appearance of these mutations was very consistent, generally occurring between 5 and 6 months following treatment. Mathematical modeling indicated that the mutations were present in expanded subclones before the initiation of panitumumab treatment. Diaz et al. (2012) suggested that the emergence of KRAS mutations is a mediator of acquired resistance to EGFR blockade and that these mutations can be detected in a noninvasive manner. The results also explained why solid tumors develop resistance to targeted therapies in a highly reproducible fashion.

Arteriovenous Malformations of the Brain

Nikolaev et al. (2018) analyzed tissue and blood samples from patients with arteriovenous malformations of the brain (BAVM; 108010) to detect somatic mutations. They performed exome DNA sequencing of BAVM tissue samples from 26 patients in the main study group and of paired blood samples from 17 of these patients, and then confirmed their findings using droplet digital PCR analysis of tissue samples from 39 patients in the initial study group (21 of whom had matching blood samples) and from 33 patients in an independent validation group. Nikolaev et al. (2018) detected somatic activating KRAS mutations gly12 to asp (G12D; 190070.0025) and gly12 to val (G12V; 190070.0026) in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from BAVM, Nikolaev et al. (2018) detected KRAS mutations and observed that expression of mutant KRAS (KRAS G12V) in endothelial cells in vitro induced increased ERK activity, increased expression of genes related to angiogenesis and Notch (190198) signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK-ERK signaling (see 176872). Nikolaev et al. (2018) concluded that they identified activating KRAS mutations in the majority of BAVM tissue samples that were analyzed, and proposed that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain epithelial cells.

Oculoectodermal Syndrome

In affected tissue from 2 patients with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) identified somatic mosaicism for 2 different missense mutations in the KRAS gene, G12D (190070.0003) and L19F (190070.0024).

In 3 unrelated children with OES, Boppudi et al. (2016) identified somatic missense mutations in the KRAS gene, A146T (190070.0027) and A146V (190070.0028), that were mosaic in lesional tissue and absent from leukocyte DNA.

In a 4-year-old Mexican girl (patient 1) and an unrelated 12-year-old Mexican boy (patient 2) with OES, Chacon-Camacho et al. (2019) identified somatic mosaicism for the previously reported KRAS variants, A146T and A146V, respectively.

Associations Pending Confirmation

For discussion of a possible association between postzygotic somatic mutation in the KRAS gene and melorheostosis, see 166700.


Genotype/Phenotype Correlations

Andreyev et al. (1997) used PCR amplification and DNA sequencing to investigate KRAS exon 1 mutations (codons 12 and 13) in histologic sections of colorectal adenocarcinomas. They examined samples from 98 patients with Dukes stage A or B fully resected colorectal cancers. Fourteen of these patients had subsequently relapsed. The presence of a KRAS mutation was not associated with tumor stage or histologic grade; neither was there any association with those patients who relapsed. The authors concluded that detection of KRAS mutation in early colorectal adenocarcinomas was of no prognostic value.

Porta et al. (1999) found that serum concentrations of organochlorine compounds were significantly higher in patients with exocrine pancreatic cancer with a codon 12 KRAS2 mutation compared to cases without a mutation, with an odds ratio of 8.7 for one organochlorine and 5.3 for another organochlorine. These estimates held after adjusting for total lipids, other covariates, and total polychlorinated biphenyls (PCBs). A specific association was observed between the G12V (190070.0006) mutation and both organochlorine concentrations, with an odds ratio of 15.9 and 24.1 for each of the compounds. A similar pattern was shown for the major diorthochlorinated PCBs.

Vasko et al. (2003) performed a pooled analysis of 269 mutations in HRAS, KRAS, and NRAS garnered from 39 previous studies of thyroid tumors. Mutations in codon 61 of NRAS were significantly more frequent in follicular tumors (19%) than in papillary tumors (see 188550) (5%) and significantly more frequent in malignant (25%) than in benign (14%) tumors. HRAS mutations in codons 12/13 were found in 2 to 3% of all types of tumors, but HRAS mutations in codon 61 were observed in only 1.4% of tumors, and almost all of them were malignant. KRAS mutations in exon 1 were found more often in papillary than follicular cancers (2.7% vs 1.6%) and were sometimes correlated with special epidemiologic circumstances. The second part of the study by Vasko et al. (2003) involved analysis of 80 follicular tumors from patients living in Marseille (France) and Kiev (Ukraine). HRAS mutations in codons 12/13 were found in 12.5% of common adenomas and in 1 follicular carcinoma (2.9%). Mutations in codon 61 of NRAS occurred in 23.3% and 17.6% of atypical adenomas and follicular carcinomas, respectively.


Population Genetics

Although several studies confirmed that approximately 40% of primary colorectal adenocarcinomas in humans contain a mutated form of the KRAS2 gene, the patterns of mutation at codons 12, 13, and 61 are not the same in different populations. Hayashi et al. (1996) used the MASA method to analyze the frequency and type of point mutations in these 3 codons in 319 colorectal cancer tissues collected from patients in Japan. They then compared these results with those from other sources to examine whether different geographic locations and environmental influences might impose distinct patterns on the spectrum of KRAS mutations. Comparing findings in the U.S., France, and Yugoslavia with those in Japan, a number of significant differences were found. A possible explanation put forth by Hayashi et al. (1996) was that an environmental carcinogen prevailing in a geographic region combines with the susceptibility of a particular tissue to dictate which type of DNA lesion will predominate. The predominance of G-to-A mutations among American and Japanese colorectal cancer patients could be attributable to alkylating agents or to the absence of direct interaction with any carcinogens. The prevalence of G-to-T mutations among Yugoslav and French patients might be ascribed to polycyclic aromatic hydrocarbons and heterocyclic amines.


Animal Model

Muller et al. (1983) found transcription of KRAS and the McDonough strain of feline sarcoma virus (FMS) gene (see 164770) during mouse development. Furthermore, the differences in transcription in different tissues suggested a specific role for each: FMS was expressed in extraembryonic structures or in transport in these tissues, whereas KRAS was expressed ubiquitously.

Holland et al. (2000) transferred, in a tissue-specific manner, genes encoding activated forms of Ras and Akt (164730) to astrocytes and neural progenitors in mice. Although neither activated Ras nor Akt alone was sufficient to induce glioblastoma multiforme (GBM; 137800) formation, the combination of activated Ras and Akt induced high-grade gliomas with the histologic features of human GBMs. These tumors appeared to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs, and Holland et al. (2000) demonstrated that AKT activity is increased in most of these tumors, implying that combined activation of these 2 pathways accurately models the biology of this disease.

Johnson et al. (2001) used a variation of 'hit-and-run' gene targeting to create mouse strains carrying oncogenic alleles of Kras capable of activation only on a spontaneous recombination event in the whole animal. They demonstrated that mice carrying these mutations were highly predisposed to a range of tumor types, predominantly early-onset lung cancer. This model was further characterized by examining the effects of germline mutations in the p53 gene (191170), which is known to be mutated along with KRAS in human tumors. Johnson et al. (2001) concluded that their approach had several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.

Zhang et al. (2001) presented evidence of a tumor suppressor role of wildtype KRAS2 in lung tumorigenesis. They found that heterozygous Kras2-deficient mice were highly susceptible to the chemical induction of lung tumors compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells. Allelic loss of wildtype Kras2 was found in 67 to 100% of chemically induced mouse lung adenocarcinomas that harbored a mutant Kras2 allele. These and other data strongly suggested that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression. Pfeifer (2001) commented on these findings as representing 'a new verdict for an old convict.' He quoted evidence that the HRAS1 gene may also function as a tumor suppressor. Pfeifer (2001) noted an interesting parallel to the p53 tumor suppressor, which was initially described as an oncogene, carrying point mutations in tumors. Later it was discovered that it is, in fact, the wildtype copy of the gene that functions as a tumor suppressor gene and is capable of reducing cell proliferation.

Costa et al. (2002) crossed Nf1 (613113) heterozygote mice with mice heterozygous for a null mutation in the Kras gene. Double heterozygotes with decreased Ras function had improved learning relative to Nf1 heterozygote mice. Costa et al. (2002) also showed that the Nf1 +/- mice have increased GABA-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Costa et al. (2002) concluded that learning deficits associated with Nf1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition.

An S17N substitution in any of the RAS proteins produces dominant-inhibitory proteins with higher affinities for exchange factors than normal RAS. These mutants cannot interact with downstream effectors and therefore form unproductive complexes, preventing activation of endogenous RAS. Using experiments in COS-7 cells, mouse fibroblasts, and canine kidney cells, Matallanas et al. (2003) found that the Hras, Kras, and Nras S17N mutants exhibited distinct inhibitory effects that appeared to be due largely to their specific membrane localizations. The authors demonstrated that Hras is present in caveolae, lipid rafts, and bulk disordered membranes, whereas Kras and Nras are present primarily in disordered membranes and lipid rafts, respectively. Thus, the Hras S17N mutant inhibited activation of all 3 wildtype RAS isoforms, the Kras S17N mutant inhibited wildtype Kras and the portion of Hras in disordered membranes, and the Nras S17N mutant inhibited wildtype Nras and the portion of Hras in lipid rafts.

By delivering a recombinant adenoviral vector expressing Cre recombinase to the bursal cavity that encloses the ovary, Dinulescu et al. (2005) expressed an oncogenic Kras allele within the ovarian surface epithelium and observed benign epithelial lesions with a typical endometrioid glandular morphology that did not progress to ovarian carcinoma (167000); 7 of 15 mice (47%) also developed peritoneal endometriosis (131200). When the Kras mutation was combined with conditional deletion of Pten (601728), all mice developed invasive endometrioid ovarian adenocarcinomas. Dinulescu et al. (2005) stated that these were the first mouse models of endometriosis and endometrioid adenocarcinoma of the ovary.

Collado et al. (2005) used a mouse model for cancer initiation in humans: the animals had a conditional oncogenic K-rasV12 (190070.0006) allele that is activated only by the enzyme Cre recombinase, causing them to develop multiple lung adenomas (premalignant tumors) and a few lung adenocarcinomas (malignant tumors). Senescence markers previously identified in cultured cells were used to detect oncogene-induced senescence in lung sections from control mice (expressing Cre) and from K-rasV12-expressing mice (expressing Cre and activated K-rasV12). Collado et al. (2005) analyzed p16(INK4a) (600160), an effector of in vitro oncogene-induced senescence, and de novo markers that were identified by using DNA microarray analysis of in vitro oncogene-induced senescence. These de novo markers are p15(INK4b), also known as CDKN2B (600431), DEC1 (BHLHB2; 604256), and DCR2 (TNFRSF10D; 603614). Staining with antibodies against p16(INK4a), p15(INK4b), DEC1, and DCR2 revealed abundant positive cells in adenomas, whereas adenocarcinomas were essentially negative. By contrast, the proliferation marker Ki-67 revealed a weak proliferative index in adenomas compared with adenocarcinomas. Collado et al. (2005) concluded that oncogene-induced senescence may help to restrict tumor progression. They concluded that a substantial number of cells in premalignant tumors undergo oncogene-induced senescence, but that cells in malignant tumors are unable to do this owing to the loss of oncogene-induced senescence effectors such as p16(INK4a) or p53.

Using an Hras (190020) knockin mouse model, To et al. (2008) demonstrated that specificity for Kras mutations in lung and Hras mutations in skin tumors is determined by local regulatory elements in the target Ras genes. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele. Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications. To et al. (2008) concluded that their findings may have implications for the design of therapeutic strategies for inhibiting oncogenic Kras activity in human cancers.

Junttila et al. (2010) modeled the probable therapeutic impact of p53 (191170) restoration in a spontaneously evolving mouse model of nonsmall cell lung cancer (NSCLC) initiated by sporadic oncogenic activation of endogenous KRAS developed by Jackson et al. (2001). Surprisingly, p53 restoration failed to induce significant regression of established tumors, although it did result in a significant decrease in the relative proportion of high-grade tumors. This was due to selective activation of p53 only in the more aggressive tumor cells within each tumor. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signaling sensor p19(ARF) (600160). Junttila et al. (2010) concluded that p53-mediated tumor suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumor evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

A single endogenous mutant Kras allele is sufficient to promote lung tumor formation in mice, but malignant progression requires additional genetic alterations. Junttila et al. (2010) showed that advanced lung tumors from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) (see 190070.0005) allelic enrichment (Kras(G12D)/Kras(wildtype) greater than 1), implying that mutant Kras copy gains are positively selected during progression. Through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, Kerr et al. (2016) demonstrated that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channeling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous nonsmall cell lung cancer cells and in vivo, and in spontaneous advanced murine lung tumors (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumors (Kras(G12D) heterozygous). Finally, Kerr et al. (2016) demonstrated that mutant Kras copy gain creates unique metabolic dependencies that can be exploited to selectively target these aggressive mutant Kras tumors. The authors concluded that mutant Kras lung tumors are not a single disease but rather a heterogeneous group comprising 2 classes of tumors with distinct metabolic profiles, prognosis, and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content.


ALLELIC VARIANTS 28 Selected Examples):

.0001   LUNG CANCER, SOMATIC

KRAS, GLY12CYS
SNP: rs121913530, gnomAD: rs121913530, ClinVar: RCV000013406, RCV000038265, RCV000119791, RCV000418063, RCV000420450, RCV000431049, RCV000435281, RCV001292543, RCV001355787, RCV003654176

In a cell line of human lung cancer (211980), Nakano et al. (1984) identified a 34G-T transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-cys (G12C) substitution. Studies of the mutant protein showed that it had transforming abilities consistent with activation of the gene.

In a study of 106 prospectively enrolled patients with primary adenocarcinoma of the lung, Ahrendt et al. (2001) found that 92 (87%) were smokers. KRAS2 mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS2 mutations had 1 of 4 changes in codon 12, the most common being G12C, which was present in 25 tumors.

Inhibitor of KRAS(G12C)

Canon et al. (2019) optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity to knockdown KRAS carrying the G12C variant. Canon et al. (2019) discovered the KRAS(G12C) inhibitor AMG-510 and presented data on its preclinical activity. Treatment with AMG-510 led to the regression of KRAS(G12C) tumors and improved the antitumor efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG-510 resulted in a proinflammatory tumor microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS(G12D) tumors, which suggested adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG-510 demonstrated antitumor activity in the first dosing cohorts and represented a potentially transformative therapy for patients for whom effective treatments are lacking.

Janne et al. (2022) conducted a phase 2 cohort study to evaluate the clinical efficacy of oral adagrasib, a selective covalent KRAS(G12C) inhibitor, among patients with KRAS(G12C)-mutated nonsmall cell lung cancer who were previously treated with platinum-based chemotherapy and antiprogrammed death 1 or programmed ligand 1 therapy. Among the 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response by blinded independent review. The median duration of response was 8.5 months, with a median progression-free survival of 6.5 months and median overall survival of 12.6 months at last follow-up. Treatment-related adverse events of grade 3 or higher occurred in 44.8%, resulting in a treatment discontinuation rate of 6.9%.


.0002   LUNG CANCER, SQUAMOUS CELL, SOMATIC

BLADDER CANCER, SOMATIC, INCLUDED
KRAS, GLY12ARG
SNP: rs121913530, gnomAD: rs121913530, ClinVar: RCV000013407, RCV000013408, RCV000154401, RCV000422773, RCV000433472, RCV000441777, RCV000585776, RCV001356365, RCV002513010

In a squamous cell lung carcinoma (211980) from a 66-year-old man, Santos et al. (1984) identified a G-to-C transversion in exon 1 of the KRAS2 gene, resulting in a gly12-to-arg (G12R) substitution. The mutation was not identified in the patient's normal bronchial and pulmonary parenchymal tissues or blood lymphocytes. This mutation had previously been identified in a bladder cancer (109800) and a lung cancer.


.0003   BREAST ADENOCARCINOMA, SOMATIC

JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED
OCULOECTODERMAL SYNDROME, SOMATIC, INCLUDED
KRAS, GLY13ASP
SNP: rs112445441, gnomAD: rs112445441, ClinVar: RCV000013409, RCV000038269, RCV000144967, RCV000144968, RCV000421576, RCV000427102, RCV000431806, RCV000444192, RCV000791297, RCV001092389, RCV001266168, RCV001526657, RCV001813183, RCV001839444, RCV001857340, RCV003924829

Breast Adenocarcinoma, Somatic

In a cell line from a human breast adenocarcinoma (114480), Kozma et al. (1987) identified a heterozygous G-to-A transition in exon 1 of the KRAS2 gene, resulting in a gly13-to-asp (G13D) substitution and activation of the protein.

Juvenile Myelomonocytic Leukemia, Somatic

In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G13D mutation in the KRAS gene.

RAS-associated Autoimmune Leukoproliferative Disorder, Somatic

In 2 unrelated children with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Takagi et al. (2011) identified a somatic heterozygous G13D mutation in the KRAS gene. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes. Takagi et al. (2011) noted that the same somatic mutation had been found in patients with JMML, and they postulated that the variable clinical and hematologic features of the 2 disorders may be related to the stage of differentiation at which the KRAS mutation is acquired.

Oculoectodermal Syndrome

In a patient (patient 1) with oculoectodermal syndrome (OES; 600268), Peacock et al. (2015) performed whole-genome shotgun sequencing to compare DNA from the patient's femur nonossifying fibroma (NOF) with DNA from her peripheral blood, and identified the G13D mutation (c.38G-A, NM_033360.3) in the KRAS gene. The mutation was confirmed by both Sanger and next-generation sequencing (allelic frequency, 32.9%). The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples (allelic frequencies, 10.3-38.8%), but not in her bone marrow or peripheral blood.


.0004   BLADDER CANCER, TRANSITIONAL CELL, SOMATIC

KRAS, ALA59THR
SNP: rs121913528, ClinVar: RCV000013410, RCV000423066

In a human transitional cell bladder carcinoma cell line (109800), Grimmond et al. (1992) identified a heterozygous G-to-A transition in the KRAS2 gene, resulting in an ala59-to-thr (A59T) substitution. The mutation was present in paraffin-embedded tissue from the primary tumor of the patient.


.0005   PANCREATIC CARCINOMA, SOMATIC

GASTRIC CANCER, SOMATIC, INCLUDED
EPIDERMAL NEVUS, SOMATIC, INCLUDED
NEVUS SEBACEOUS, SOMATIC, INCLUDED
SCHIMMELPENNING-FEUERSTEIN-MIMS SYNDROME, SOMATIC MOSAIC, INCLUDED
JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC, INCLUDED
KRAS, GLY12ASP
SNP: rs121913529, gnomAD: rs121913529, ClinVar: RCV000013411, RCV000022799, RCV000029214, RCV000029215, RCV000144969, RCV000144970, RCV000150896, RCV000150897, RCV000272938, RCV000425250, RCV000426369, RCV000433573, RCV000443973, RCV000548006, RCV000585796, RCV000662266, RCV000856666, RCV001799604, RCV001839445, RCV002508117, RCV003327361

Pancreatic Carcinoma, Somatic

Motojima et al. (1993) identified mutations in KRAS codon 12 in 46 of 53 pancreatic carcinomas (260350). In 2 of these 46 tumors, the mutations were gly12-to-asp (G12D) and gly12-to-val (G12V; 190070.0006), respectively.

Gastric Cancer, Somatic

Lee et al. (1995) found mutations in codon 12 of the KRAS gene in 9 of 140 cases of gastric cancer (613659); 2 cases had G12D.

Epidermal Nevus, Somatic

Bourdeaut et al. (2010) found somatic mosaicism for the G12D mutation in a female infant with an epidermal nevus (162900) who developed a uterovaginal rhabdomyosarcoma at age 6 months. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes. No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway.

Hafner et al. (2012) identified a somatic G12D mutation in 1 of 72 keratinocytic epidermal nevi.

Nevus Sebaceous, Somatic

Groesser et al. (2012) identified a somatic G12D mutation in 2 of 65 (3%) nevus sebaceous tumors (see 162900). One of the tumors also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).

Schimmelpenning-Feuerstein-Mims Syndrome, Somatic Mosaic

The KRAS G12D mutation was also found in somatic mosaic state in a patient with Schimmelpenning-Feuerstein-Mims syndrome (163200) who was originally reported by Rijntjes-Jacobs et al. (2010). Groesser et al. (2012) postulated that the mosaic mutation likely extends to extracutaneous tissues in that disorder, which could explain the phenotypic pleiotropy.

Juvenile Myelomonocytic Leukemia, Somatic

In white blood cells derived from a 22-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12D mutation in the KRAS gene.

RAS-associated Autoimmune Leukoproliferative Disorder, Somatic

In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous G12D mutation in the KRAS gene.


.0006   PANCREATIC CARCINOMA, SOMATIC

NEVUS SEBACEOUS, SOMATIC, INCLUDED
KRAS, GLY12VAL
SNP: rs121913529, gnomAD: rs121913529, ClinVar: RCV000013413, RCV000029216, RCV000150895, RCV000154262, RCV000157944, RCV000417765, RCV000428010, RCV000439101, RCV000439750, RCV000585801, RCV002291496, RCV003322589, RCV003455987, RCV003539760

Pancreatic Carcinoma, Somatic

For discussion of the gly12-to-val (G12V) substitution that was found in 1 of 53 pancreatic carcinomas (260350) by Motojima et al. (1993), see 190070.0005.

Nevus Sebaceous, Somatic

Groesser et al. (2012) identified a somatic G12V mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900). The tumor also carried a somatic mutation in the HRAS gene (G13R; 190020.0017).


.0007   GASTRIC CANCER, SOMATIC

JUVENILE MYELOMONOCYTIC LEUKEMIA, SOMATIC, INCLUDED
KRAS, GLY12SER
SNP: rs121913530, gnomAD: rs121913530, ClinVar: RCV000013414, RCV000038264, RCV000119790, RCV000144971, RCV000432392, RCV000445081, RCV000782191, RCV001851824

Gastric Cancer, Somatic

Lee et al. (1995) found mutations in codon 12 of the KRAS2 gene in 9 of 140 cases of gastric cancer (613659); 7 cases had a G-to-A transition, resulting in a gly12-to-ser (G12S) substitution.

Juvenile Myelomonocytic Leukemia, Somatic

In white blood cells derived from a 4-month-old girl with juvenile myelomonocytic leukemia (JMML; 607785), Matsuda et al. (2007) identified a somatic heterozygous G12S mutation in the KRAS gene.


.0008   LEUKEMIA, ACUTE MYELOGENOUS, SOMATIC

KRAS, 3-BP INS, GLY11INS
SNP: rs606231202, ClinVar: RCV000013415

In the bone marrow of a 4-year-old child with acute myeloid leukemia (AML; 601626), Bollag et al. (1996) identified an in-frame 3-bp insertion in exon 1 of the KRAS2 gene, resulting in an insertion of gly11. Expression of the mutant protein in NIH 3T3 cells caused cellular transformation, and expression in COS cells activated the RAS-mitogen-activated protein kinase signaling pathway. RAS-GTP levels measured in COS cells established that this novel mutant accumulates up to 90% in the GTP state, considerably higher than a residue 12 mutant. This mutation was the first dominant RAS mutation found in human cancer that did not involve residues 12, 13, or 61.


.0009   CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, GLY60ARG
SNP: rs104894359, ClinVar: RCV000013416, RCV000157935, RCV000254661, RCV000521390, RCV000844635, RCV001267316, RCV003313917

In an individual with cardiofaciocutaneous syndrome (CFC2; 615278), Niihori et al. (2006) identified a heterozygous 178G-C transversion in exon 2 of the KRAS2 gene, predicting a gly60-to-arg (G60R) substitution.


.0010   CARDIOFACIOCUTANEOUS SYNDROME 2

NOONAN SYNDROME 3, INCLUDED
KRAS, ASP153VAL
SNP: rs104894360, ClinVar: RCV000013417, RCV000013418, RCV000157940, RCV000212501, RCV000507330, RCV000523200, RCV000763307, RCV000844634, RCV001267227, RCV003450634

Cardiofaciocutaneous Syndrome 2

In 2 unrelated individuals with cardiofaciocutaneous syndrome (CFC2; 615278), Niihori et al. (2006) identified a heterozygous 458A-T transversion in exon 4b of the KRAS2 gene, predicting an asp153-to-val (D153V) substitution. The D153V mutation was identified in DNA extracted from both blood and buccal cells of 1 of the individuals. This heterozygous mutation and G60R (190070.0009) were not found in 100 control chromosomes and were not found in any parent. The results suggested that these germline mutations occurred de novo.

Noonan Syndrome 3

Schubbert et al. (2006) found the D153V mutation in a patient who had been diagnosed with Noonan syndrome-3 (NS3; 609942). The 18-year-old male had hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse, Noonan-like features, short stature, mild pectus carinatum, unilateral cryptorchidism, mild developmental delay, and grand mal seizures.


.0011   NOONAN SYNDROME 3

KRAS, THR58ILE
SNP: rs104894364, ClinVar: RCV000013419, RCV000157933, RCV000211785, RCV000704828

In a 3-month-old female with Noonan syndrome-3 (NS3; 609942), Schubbert et al. (2006) identified a heterozygous 173C-T transition in the KRAS2 gene, resulting in a thr58-to-ile (T58I) substitution. The child had a severe clinical phenotype and presented with a myeloproliferative disorder of the juvenile myelomonocytic leukemia (JMML; 607785) type. The mutation was present in the patient's buccal cells but was absent in parental DNA. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis.

Kratz et al. (2009) identified a de novo heterozygous T58I mutation in a patient with Noonan syndrome who also had craniosynostosis, suggesting a genotype/phenotype correlation. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure.


.0012   NOONAN SYNDROME 3

KRAS, VAL14ILE
SNP: rs104894365, gnomAD: rs104894365, ClinVar: RCV000013420, RCV000119792, RCV000157945, RCV000212499, RCV000521254, RCV000844637, RCV001266727, RCV001813184

In 3 unrelated patients with Noonan syndrome-3 (NS3; 609942), Schubbert et al. (2006) identified a heterozygous 40G-A transition in the KRAS2 gene, resulting in a val14-to-ile (V14I) substitution. Each individual showed a mild clinical phenotype, and none had a history of myeloproliferative disorder or cancer. The patients were from a group of Noonan syndrome patients studied who did not have mutation in the PTPN11 gene (176876)


.0013   CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, PRO34ARG
SNP: rs104894366, ClinVar: RCV000043674, RCV000207495, RCV000211723, RCV000850569, RCV001851825

In a 13-year-old female with the diagnosis of cardiofaciocutaneous syndrome (CFC2; 615278), Schubbert et al. (2006) found a heterozygous pro34-to-arg (P34R) mutation in the KRAS2 gene. The patient had pulmonic stenosis, left ventricular hypertrophy, Noonan-like facial features, short stature, short neck, broad thorax, lymphedema, chylothorax, left ptosis, severe developmental delay, and agenesis of the corpus callosum.


.0014   NOONAN SYNDROME 3

KRAS, VAL152GLY
SNP: rs104894367, ClinVar: RCV000013422

In a 1-year-old girl with the diagnosis of Noonan syndrome-3 (NS3; 609942), Carta et al. (2006) identified a 455T-G transversion in the KRAS2 gene, resulting in a val152-to-gly (V152G) substitution. The patient had macrocephaly with high and broad forehead, curly and sparse hair, hypertelorism, strabismus, epicanthic folds, downslanting palpebral fissures, hypoplastic nasal bridge with bulbous tip of the nose, high palate and macroglossia, low-set and posteriorly rotated ears, short neck with redundant skin, wide-set nipples, and umbilical hernia. She had been born at 32 weeks' gestation by cesarean section after a pregnancy complicated by a cystic hygroma detected at 12 weeks and polyhydramnios at 30 weeks. At birth she showed edema of the lower limbs. The phenotype showed features overlapping Costello syndrome (218040) (polyhydramnios, neonatal macrosomia, and macrocephaly, loose skin, and severe failure to thrive) and, to a lesser extent, CFC syndrome (615278) (macrocephaly and sparse hair).


.0015   NOONAN SYNDROME 3

KRAS, ASP153VAL
ClinVar: RCV000013417, RCV000013418, RCV000157940, RCV000212501, RCV000507330, RCV000523200, RCV000763307, RCV000844634, RCV001267227, RCV003450634

In a 14-year-old girl with Noonan syndrome-3 (NS3; 609942) and some features of CFC syndrome (615278), Carta et al. (2006) identified a 458A-T transversion in the KRAS2 gene, resulting in an asp153-to-val (D153V) substitution. The girl had short stature and growth retardation and delayed bone age, cardiac defects (moderate ventricular hypertrophy, mild pulmonic stenosis, and atrial septal defect), dysmorphic features (hypertelorism, downslanting palpebral fissures, strabismus, low-set and thick ears, relative macrocephaly with high forehead, and a depressed nasal bridge), short and mildly webbed neck, wide-set nipples, and developmental delay. There was hyperpigmentation of the skin and a large cafe-au-lait spot on the face. Gestation was complicated by polyhydramnios.


.0016   PILOCYTIC ASTROCYTOMA, SOMATIC

KRAS, GLY13ARG
SNP: rs121913535, gnomAD: rs121913535, ClinVar: RCV000013424, RCV000038267, RCV000426673, RCV000436657, RCV001357137

In 1 of 21 sporadic pilocytic astrocytoma (PA) (see 137800) samples, Sharma et al. (2005) identified a G-to-C transversion in the KRAS2 gene, resulting in a gly13-to-arg (G13R) substitution. The tumor arose in the cortex of an 11-year-old boy; the mutation was not identified in the germline of the patient. Immunohistochemical studies showed increased phospho-AKT (see 164730) activity compared to controls in all 21 PA samples, indicating increased activation of the Ras pathway. No mutations in the KRAS gene were observed in the other tumors, and none of the 21 tumors showed mutations in the HRAS (190020) or NRAS (164790) genes. Of note, the G13R substitution occurs in the same codon as another KRAS mutation (G13D; 190070.0003) identified in a breast carcinoma cell line.


.0017   CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, LYS5ASN
SNP: rs104894361, gnomAD: rs104894361, ClinVar: RCV000013425, RCV000153427, RCV000520745, RCV000623267

In a 7.5-month-old male infant with a clinical diagnosis of Costello syndrome (218040), Zenker et al. (2007) identified a heterozygous 15A-T transversion in exon 1 of the KRAS2 gene, resulting in a lys5-to-asn (K5N) substitution. The patient had hypertelorism, downslanting palpebral fissures, coarse facies, pectus carinatum, sparse hair, redundant skin, and moderate mental retardation. Zenker et al. (2007) noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; 615278), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020).


.0018   CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, PHE156LEU
SNP: rs104894362, ClinVar: RCV000013426, RCV000157942, RCV001205658, RCV003390676

In a male infant with a clinical diagnosis of Costello syndrome (218040) who died suddenly at age 14 months, Zenker et al. (2007) identified a heterozygous 468C-G transversion in the KRAS2 gene, resulting in a phe156-to-leu (F156L) substitution. The patient had coarse facies, cardiac defects, sparse hair, loose and redundant skin, developmental delay, and moderate mental retardation. Zenker et al. (2007) noted that the patient may later develop features of cardiofaciocutaneous syndrome (CFC2; 615278), which is commonly associated with KRAS mutations, but emphasized that the findings underscored the central role of Ras in the pathogenesis of these phenotypically related disorders.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020).


.0019   NOONAN SYNDROME 3

KRAS, LYS5GLU
SNP: rs193929331, ClinVar: RCV000013427, RCV000149836, RCV000364781, RCV000605141, RCV002291547, RCV003398495

In a 20-year-old woman with clinical features typical of Costello syndrome (218040) and additional findings seen in Noonan syndrome (NS3; 609942), Bertola et al. (2007) identified a 194A-G transition in exon 2 of the KRAS gene, resulting in a lys5-to-glu (K5E) substitution. The mutation was not found in her unaffected mother or brother or in 100 controls.

Kerr et al. (2008) commented that the diagnosis of Costello syndrome should be used only to refer to patients with mutations in the HRAS gene (190020).

Bertola et al. (2012) reported a patient with a germline K5E mutation and dysmorphic features who developed multiple diffuse schwannomas.


.0020   NOONAN SYNDROME 3

KRAS, GLY60SER
SNP: rs104894359, ClinVar: RCV000013428, RCV000157934, RCV000689097, RCV002470709

In a patient with Noonan syndrome-3 (NS3; 609942) and craniosynostosis, Kratz et al. (2009) identified a de novo heterozygous 178G-A transition in the KRAS gene, resulting in a gly60-to-ser (G60S) substitution. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure.

A mutation in this same codon (G60R; 190070.0009) has been found in a patient with cardiofaciocutaneous syndrome (CFC2; 615278).


.0021   CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, TYR71HIS
SNP: rs387907205, ClinVar: RCV000024617

In a mother and son with variable features of cardiofaciocutaneous syndrome (CFC2; 615278), Stark et al. (2012) identified a heterozygous 211T-C transition in exon 3 of the KRAS gene, resulting in a tyr71-to-his (Y71H) substitution in a highly conserved residue close to a region that is important for effector and regulator binding. The mutation was not found in 500 control individuals and was shown by in vitro studies to increase effector affinity. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse. She had attended a school for children with special needs. Both patients showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 (601097) testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The authors stated that this was the first documented vertically transmitted KRAS mutation.

Y71 is located at the end of the switch II region of KRAS. Using in vitro assays and transfected COS-7 cells, Cirstea et al. (2013) found that the Y71H mutation increased the binding affinity of KRAS for its major effector, RAF1 kinase (164760), leading to increased activation of MEK1 (176872)/MEK2 (601263) and ERK1 (601795)/ERK2 (176948), irrespective of stimulation. The mutation did not alter the rate of nucleotide dissociation by KRAS.


.0022   CARDIOFACIOCUTANEOUS SYNDROME 2

KRAS, LYS147GLU
SNP: rs387907206, ClinVar: RCV000024618, RCV000520244

In a girl with variable features of cardiofaciocutaneous syndrome (CFC2; 615278), Stark et al. (2012) identified a de novo heterozygous 439A-G transition in exon 4 of the KRAS gene, resulting in a lys147-to-glu (K147E) substitution in a highly conserved residue close to known mutations. Lys147 is part of a motif involved in the binding network for guanine nucleotides, which determine the activation state of RAS proteins. In vitro studies demonstrated that the K147E mutant protein predominates in the active GTP-bound form, probably due to facilitated uncatalyzed GDP/GTP exchange. The patient was 1 of a female dizygotic twin pair; the other twin was unaffected. The patient had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome. Reexamination at age 3.5 years showed coarser facial features more consistent with CFC. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development.

K147 is a conserved amino acid within a motif required for guanine base binding by KRAS. K147 is also ubiquitinated, leading to increased KRAS activation by GEF proteins. Using in vitro assays and transfected COS-7 cells, Cirstea et al. (2013) found that the K147E mutation significantly increased nucleotide dissociation in KRAS, generating a self-activating protein that acted independently of upstream signaling. However, overactivity of K147E mutant KRAS was subject to normal downregulation by RasGAP (see 139150) and had 2-fold lower affinity for RAF1 kinase (164760).


.0023   RAS-ASSOCIATED AUTOIMMUNE LEUKOPROLIFERATIVE DISORDER, SOMATIC

KRAS, GLY13CYS
SNP: rs121913535, gnomAD: rs121913535, ClinVar: RCV000038268, RCV000144972, RCV000443868, RCV000681039, RCV003335071

In hematologic cells derived from a girl with RAS-associated autoimmune leukoproliferative disorder (RALD; 614470), Niemela et al. (2010) identified a somatic heterozygous c.37G-T transversion in the KRAS gene, resulting in a gly13-to-cys (G13C) substitution. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function.


.0024   OCULOECTODERMAL SYNDROME, SOMATIC

KRAS, LEU19PHE
SNP: rs121913538, gnomAD: rs121913538, ClinVar: RCV000201922, RCV000441871, RCV001839449, RCV003654222

In a 25-year-old man with oculoectodermal syndrome (OES; 600268), who was one of the original boys (patient 2) with OES described by Toriello et al. (1993), Peacock et al. (2015) identified heterozygosity for a somatic c.57G-C transversion (c.57G-C, NM_033360.3) in the KRAS gene, resulting in a leu19-to-phe (L19F) substitution (allelic frequency, 16.9%). The mutation was also found in samples from the patient's skin, bone marrow from proximal femur, and peripheral blood (allelic frequencies, 4.7-10.3%).


.0025   ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC

KRAS, GLY12ASP
ClinVar: RCV000013411, RCV000022799, RCV000029214, RCV000029215, RCV000144969, RCV000144970, RCV000150896, RCV000150897, RCV000272938, RCV000425250, RCV000426369, RCV000433573, RCV000443973, RCV000548006, RCV000585796, RCV000662266, RCV000856666, RCV001799604, RCV001839445, RCV002508117, RCV003327361

Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-asp (G12D, c.35G-A) mutation in a total of 32 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant (190070.0026) were present in 2.4 to 4.0% of the sequence reads per sample. The G12D mutation drove MAPK-ERK activity in endothelial cells.


.0026   ARTERIOVENOUS MALFORMATION OF THE BRAIN, SOMATIC

KRAS, GLY12VAL
ClinVar: RCV000013413, RCV000029216, RCV000150895, RCV000154262, RCV000157944, RCV000417765, RCV000428010, RCV000439101, RCV000439750, RCV000585801, RCV002291496, RCV003322589, RCV003455987, RCV003539760

Using exome DNA sequencing and droplet digital PCR analysis, Nikolaev et al. (2018) identified a gly12-to-val (G12D, c.35G-T) mutation in a total of 13 of 72 arteriovenous malformations of the brain (BAVM; 108010), and in none of 21 paired blood samples. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12D variant (190070.0025) were present in 2.4 to 4.0% of the sequence reads per sample. The G12V mutation drove MAPK-ERK activity in endothelial cells.


.0027   OCULOECTODERMAL SYNDROME, SOMATIC

KRAS, ALA146THR
SNP: rs121913527, ClinVar: RCV000178223, RCV000426420, RCV000791298, RCV001839448, RCV001852208, RCV002227934

In lesional tissues from a 6-year-old boy with oculoectodermal syndrome (OES; 600268), originally reported by Aslan et al. (2014), Boppudi et al. (2016) identified somatic mosaicism for a c.436G-A transition (c.436G-A, ENST00000311936) in the KRAS gene, resulting in an ala146-to-thr (A146T) substitution. The mutant allele frequency ranged from 11% to 38% in lesional tissue samples, and was not found in leukocyte DNA.

In a 4-year-old Mexican girl with OES (patient 1), Chacon-Camacho et al. (2019) identified somatic mosaicism for the A146T mutation in the KRAS gene. The mutant allele frequency was 28% in lesional tissue, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells.


.0028   OCULOECTODERMAL SYNDROME, SOMATIC

KRAS, ALA146VAL
SNP: rs1057519725, ClinVar: RCV000423608, RCV000434735, RCV000441300, RCV000791299, RCV001839452, RCV002524688, RCV003332167, RCV003488585

In 2 unrelated children with oculoectodermal syndrome (OES; 600268), Boppudi et al. (2016) identified somatic mosaicism for a c.437C-T transition (c.437C-T, ENST00000311936) in the KRAS gene, resulting in an ala146-to-val (A146V) substitution. The mutant allele frequency ranged from less than 10% to 40% in lesional tissue samples, and was not found in leukocyte DNA.

In a 12-year-old Mexican boy with OES (patient 2), Chacon-Camacho et al. (2019) identified somatic mosaicism for the A146V mutation in the KRAS gene. The mutant allele frequency was 26% to 27% in lesional tissues, and the variant was not detected in DNA isolated from blood leukocytes or buccal cells.


See Also:

Capon et al. (1983); Der and Cooper (1983); Sakaguchi et al. (1984); Shimizu et al. (1983)

REFERENCES

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Contributors:
Sonja A. Rasmussen - updated : 07/25/2022
Bao Lige - updated : 03/09/2022
Ada Hamosh - updated : 05/13/2020
Ada Hamosh - updated : 12/10/2019
Ada Hamosh - updated : 09/12/2019
Marla J. F. O'Neill - updated : 08/01/2019
Ada Hamosh - updated : 03/06/2018
Ada Hamosh - updated : 09/30/2016
Ada Hamosh - updated : 02/17/2016
Nara Sobreira - updated : 11/11/2015
Cassandra L. Kniffin - updated : 11/12/2014
Patricia A. Hartz - updated : 5/23/2014
Ada Hamosh - updated : 12/6/2013
Ada Hamosh - updated : 7/9/2013
Ada Hamosh - updated : 7/8/2013
Cassandra L. Kniffin - updated : 1/30/2013
Cassandra L. Kniffin - updated : 7/25/2012
Ada Hamosh - updated : 7/17/2012
Cassandra L. Kniffin - updated : 6/28/2012
Marla J. F. O'Neill - updated : 11/29/2011
Cassandra L. Kniffin - updated : 2/21/2011
Ada Hamosh - updated : 2/3/2011
Ada Hamosh - updated : 8/17/2010
Ada Hamosh - updated : 3/9/2010
Ada Hamosh - updated : 12/29/2009
Cassandra L. Kniffin - updated : 10/27/2009
Ada Hamosh - updated : 10/13/2009
Marla J. F. O'Neill - updated : 6/1/2009
Cassandra L. Kniffin - updated : 3/3/2009
Ada Hamosh - updated : 1/20/2009
Ada Hamosh - updated : 7/29/2008
Cassandra L. Kniffin - updated : 3/17/2008
Ada Hamosh - updated : 11/12/2007
George E. Tiller - updated : 4/5/2007
Cassandra L. Kniffin - reorganized : 3/8/2007
Cassandra L. Kniffin - updated : 3/2/2007
Cassandra L. Kniffin - updated : 2/15/2007
Ada Hamosh - updated : 2/8/2007
Ada Hamosh - updated : 11/28/2006
Victor A. McKusick - updated : 6/13/2006
Patricia A. Hartz - updated : 4/10/2006
Patricia A. Hartz - updated : 3/28/2006
Victor A. McKusick - updated : 2/24/2006
Ada Hamosh - updated : 9/7/2005
Stylianos E. Antonarakis - updated : 3/28/2005
Marla J. F. O'Neill - updated : 3/22/2005
Victor A. McKusick - updated : 12/16/2003
John A. Phillips, III - updated : 9/2/2003
John A. Phillips, III - updated : 9/2/2003
Ada Hamosh - updated : 9/17/2002
Victor A. McKusick - updated : 8/15/2002
Victor A. McKusick - updated : 12/13/2001
Victor A. McKusick - updated : 9/26/2001
Victor A. McKusick - updated : 9/4/2001
Victor A. McKusick - updated : 8/24/2001
Ada Hamosh - updated : 4/23/2001
Ada Hamosh - updated : 4/28/2000
Ada Hamosh - updated : 2/11/2000
Paul Brennan - updated : 7/31/1998
Victor A. McKusick - updated : 3/27/1998
Paul Brennan - updated : 11/14/1997
Victor A. McKusick - edited : 3/3/1997
Mark H. Paalman - edited : 1/10/1997

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
carol : 07/26/2022
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carol : 11/04/2021
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alopez : 06/22/2020
alopez : 05/13/2020
alopez : 12/10/2019
carol : 10/02/2019
alopez : 09/12/2019
alopez : 08/01/2019
alopez : 08/01/2019
carol : 07/24/2019
carol : 07/23/2019
carol : 03/07/2018
alopez : 03/06/2018
carol : 08/24/2017
alopez : 09/30/2016
carol : 09/02/2016
alopez : 02/17/2016
carol : 11/11/2015
alopez : 8/31/2015
carol : 11/18/2014
mcolton : 11/13/2014
ckniffin : 11/12/2014
mgross : 5/23/2014
mgross : 5/23/2014
mcolton : 5/22/2014
mcolton : 5/22/2014
alopez : 12/6/2013
alopez : 7/9/2013
alopez : 7/9/2013
alopez : 7/8/2013
alopez : 6/20/2013
alopez : 2/6/2013
ckniffin : 1/30/2013
carol : 7/26/2012
carol : 7/26/2012
carol : 7/25/2012
ckniffin : 7/25/2012
alopez : 7/19/2012
terry : 7/17/2012
terry : 7/3/2012
carol : 7/2/2012
ckniffin : 6/28/2012
terry : 4/9/2012
alopez : 3/7/2012
carol : 12/8/2011
carol : 11/29/2011
terry : 3/10/2011
wwang : 3/1/2011
ckniffin : 2/21/2011
alopez : 2/7/2011
alopez : 2/7/2011
alopez : 2/7/2011
alopez : 2/7/2011
terry : 2/3/2011
terry : 11/3/2010
alopez : 8/20/2010
terry : 8/17/2010
alopez : 3/9/2010
terry : 3/9/2010
alopez : 1/6/2010
terry : 12/29/2009
carol : 11/23/2009
carol : 11/23/2009
wwang : 11/6/2009
ckniffin : 10/27/2009
alopez : 10/23/2009
terry : 10/13/2009
joanna : 9/14/2009
wwang : 6/3/2009
terry : 6/1/2009
wwang : 3/5/2009
ckniffin : 3/3/2009
alopez : 2/6/2009
carol : 2/6/2009
terry : 1/20/2009
alopez : 7/31/2008
terry : 7/29/2008
wwang : 3/19/2008
ckniffin : 3/17/2008
alopez : 11/14/2007
alopez : 11/14/2007
terry : 11/12/2007
carol : 9/10/2007
carol : 9/6/2007
alopez : 4/13/2007
terry : 4/5/2007
carol : 3/8/2007
carol : 3/8/2007
ckniffin : 3/8/2007
ckniffin : 3/2/2007
wwang : 2/19/2007
ckniffin : 2/15/2007
alopez : 2/8/2007
alopez : 2/8/2007
alopez : 2/8/2007
terry : 2/1/2007
alopez : 12/7/2006
terry : 11/28/2006
alopez : 6/16/2006
terry : 6/13/2006
mgross : 4/14/2006
terry : 4/10/2006
wwang : 3/30/2006
terry : 3/28/2006
alopez : 3/3/2006
terry : 2/24/2006
alopez : 9/14/2005
terry : 9/7/2005
alopez : 7/14/2005
carol : 5/27/2005
mgross : 3/28/2005
tkritzer : 3/22/2005
tkritzer : 12/16/2003
cwells : 11/6/2003
alopez : 9/2/2003
alopez : 9/2/2003
terry : 1/2/2003
terry : 11/22/2002
alopez : 9/17/2002
tkritzer : 8/21/2002
tkritzer : 8/19/2002
terry : 8/15/2002
terry : 3/5/2002
alopez : 2/5/2002
alopez : 1/22/2002
carol : 1/3/2002
mcapotos : 12/19/2001
terry : 12/13/2001
carol : 10/4/2001
mcapotos : 10/3/2001
terry : 9/26/2001
alopez : 9/4/2001
alopez : 8/27/2001
terry : 8/24/2001
alopez : 4/25/2001
terry : 4/23/2001
alopez : 5/1/2000
terry : 4/28/2000
alopez : 2/15/2000
terry : 2/11/2000
mgross : 6/22/1999
alopez : 9/22/1998
alopez : 9/22/1998
terry : 7/24/1998
dkim : 7/23/1998
psherman : 3/27/1998
dholmes : 3/6/1998
alopez : 11/26/1997
alopez : 11/26/1997
alopez : 11/17/1997
alopez : 11/17/1997
alopez : 11/17/1997
alopez : 11/14/1997
mark : 3/3/1997
mark : 1/10/1997
mark : 1/10/1997
terry : 11/6/1996
terry : 10/31/1996
mark : 8/10/1995
mimadm : 6/7/1995
carol : 11/1/1993
carol : 6/30/1993
carol : 6/22/1993
carol : 6/7/1993