Alternative titles; symbols
SNOMEDCT: 254819008, 93655004; ICD10CM: C43, C43.9; ICD9CM: 172, 172.9; ORPHA: 404560, 618;
Cytogenetic location: 1p36 Genomic coordinates (GRCh38): 1:1-27,600,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36 | {Melanoma, cutaneous malignant, 1} | 155600 | Autosomal dominant | 2 |
Malignant melanoma is a neoplasm of pigment-producing cells called melanocytes that occurs most often in the skin, but may also occur in the eyes, ears, gastrointestinal tract, leptomeninges, and oral and genital mucous membranes (summary by Habif, 2010).
Genetic Heterogeneity of Susceptibility to Cutaneous Malignant Melanoma
The locus for susceptibility to familial cutaneous malignant melanoma-1 (CMM1) has been mapped to chromosome 1p36. Other CMM susceptibility loci include CMM2 (155601), caused by variation in the CDKN2A gene (600160) on chromosome 9p21; CMM3 (609048), caused by variation in the CDK4 gene (123829) on chromosome 12q14; CMM4 (608035), mapped to chromosome 1p22; CMM5 (613099), caused by variation in the MC1R gene (155555) on chromosome 16q24; CMM6 (613972), caused by variation in the XRCC3 gene (600675) on chromosome 14q32; CMM7 (612263), mapped to chromosome 20q11; CMM8 (614456), caused by variation in the MITF gene (156845) on chromosome 3p13; CMM9 (615134), caused by variation in the TERT gene (187270) on chromosome 5p15; and CMM10 (615848), caused by mutation in the POT1 gene (606478) on chromosome 7q31.
Somatic mutations causing malignant melanoma have also been identified in several genes, including BRAF (164757), STK11 (602216), PTEN (601728), TRRAP (603015), DCC (120470), GRIN2A (138253), ZNF831, BAP1 (603089), and RASA2 (601589). A large percentage of melanomas (40-60%) carry an activating somatic mutation in the BRAF gene, most often V600E (164757.0001) (Davies et al., 2002; Pollock et al., 2003).
Several writers (e.g., Moschella, 1961; Schoch, 1963; Salamon et al., 1963) commented on the usual fair complexion, blue eyes, and multiple ephelides in patients with familial melanoma.
In a questionnaire study, Kopf et al. (1986) found that a positive family history for melanoma was correlated with a younger age at first diagnosis in the proband, a smaller diameter of the lesion, lower Clark level, decreased frequency of nonmelanoma skin cancer, and reduced prevalence of noncutaneous cancer. (The Clark index refers to the level of invasion.) A comparison of monozygotic and dizygotic twins for melanoma might be important because of cases of melanoma in non-blood-related members of the same household (Robinson and Manheimer, 1972).
Lynch et al. (1978) suggested that a cutaneous marker indicative of susceptibility to malignant melanoma is characterized by large moles, variable in number, reddish brown to pink in color, and with an irregular border. Histologically, they show a bizarre intraepidermal pattern. The authors also described a melanoma family with distinctive freckling and dryness of the skin, suggesting xeroderma pigmentosum (278700) but with normal unscheduled DNA repair and a dominant pedigree pattern. Other malignancies such as colon cancer had an increased frequency in these families.
Clark et al. (1978), Greene et al. (1978), and Reimer et al. (1978) pointed out distinctive clinical and histologic features of the moles that are precursors of familial malignant melanomas. They termed these features the 'B-K mole syndrome' after the family names of 2 patients; later, Greene et al. (1980) and Elder et al. (1980) expressed a preference for the designation 'hereditary dysplastic nevus syndrome.' The same lesion underlies some cases of nonfamilial malignant melanoma. Greene et al. (1980) referred to this as 'dysplastic nevus syndrome, sporadic type.' The clinical features include between 10 and 100 moles on the upper trunk and limbs, and variability of mole size (from 5 to 15 mm), outline, and color. Histologically, B-K moles show atypical melanocytic hyperplasia, lymphocytic infiltration, delicate fibroplasia, and new blood vessel formation. Lynch et al. (1980) referred to this as FAMMM (familial atypical mole--malignant melanoma syndrome). Arndt (1984) and Greene et al. (1985) provided photographic illustration of the familial dysplastic nevus syndrome.
Lynch et al. (1980) studied 3 kindreds of the FAMMM syndrome. Father-to-son transmission was observed. One patient had 9 separate primary melanomas in 18 years. Expressivity was highly variable. Management is difficult because one cannot be certain which moles require biopsy and then, following histologic study, which require wide excision. The possibility of increased risk of cancer at other sites was raised. Hartley et al. (1987) described several cases of malignant melanoma in close relatives of children with osteosarcoma (259500) and chondrosarcoma (215300). They proposed that in certain families malignant melanoma may be a manifestation of the same gene defect that results in susceptibility to tumors characteristic of the SBLA syndrome (151623).
Tucker et al. (2002) described the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A (600160) and CDK4 (123829). They evaluated clinically and followed prospectively for up to 25 years a total of 33 families with more than 2 living members with invasive melanoma. A total of 844 family members were examined and photographed. All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either gene identified. Most of the dysplastic nevi either remained stable or regressed; few changed in a manner that should have caused concern for melanoma. The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families.
Melanoma-associated retinopathy is a form of paraneoplastic visual disorder that can occur in individuals who have metastatic cutaneous malignant melanoma. Alexander et al. (2004) found that the overall pattern of contrast sensitivity loss shown by patients with melanoma-associated retinopathy was consistent with the dysfunction at the level of the retinal bipolar cells presumed to underlie the disorder.
Tumor-specific antigens have been found in malignant melanoma (Hawkins et al., 1981; Pellegris et al., 1982).
Some studies have observed an increased risk of Parkinson disease (PD; 168600) among individuals with melanoma (see, e.g., Constantinescu et al., 2007 and Ferreira et al., 2007), suggesting that pigmentation metabolism may be involved in the pathogenesis of PD. From 2 existing study cohorts of 38,641 men and 93,661 women who were free of PD at baseline, Gao et al. (2009) found an association between decreasing darkness of natural hair color in early adulthood and increased PD risk. The pooled relative risks for PD were 1.0 (reference risk), 1.40, 1.61, and 1.93 for black, brown, blond, and red hair, respectively. These results were significant after adjusting for age, smoking, ethnicity, and other covariates. The associations between hair color and PD were particularly strong for onset before age 70 years. In a case-control study of 272 PD cases and 1,185 controls, there was an association between the cys151 SNP of the MCR1 gene (155555.0004), which confers red hair, and increased risk of PD relative to the arg151 SNP (relative risk of 3.15 for the cys/cys genotype). Noting that melanin, like dopamine, is synthesized from tyrosine, and that PD is characterized by the loss of neuromelanin-containing neurons in the substantia nigra, Gao et al. (2009) postulated a link between pigmentation and development of PD. Herrero Hernandez (2009) independently noted the association.
Multiple authors have documented familial inheritance of malignant melanoma: see Cawley (1952); Smith et al. (1966); Andrews (1968). Katzenellenbogen and Sandbank (1966) described dizygotic twins with malignant melanoma.
Anderson et al. (1967) described malignant melanoma in at least 15 members of 3 generations of 1 kindred. Early age of onset and a tendency for multiple primary lesions were features. Lynch and Krush (1968) described 2 families with malignant melanoma in 2 generations in 1 family and 3 generations in the other. Anderson (1971) reported 36 pedigrees in which a total of 106 members had cutaneous melanoma. He noted that in addition to earlier age at onset and increased frequency of multiple primary lesions, familial cases have a higher survival rate than nonfamilial cases.
Rhodes et al. (1985) found that the prevalence rate of congenital nevomelanocytic nevi was 11 times greater in sibs of probands than in the general population. They had some families with 2 generations affected.
In the families with CMM studied by Greene et al. (1983), further studies (Bale et al. (1985, 1986)) showed that dysplastic nevus (DN), a lesion known to be a precursor of melanoma, also segregates in an autosomal dominant manner. Pascoe (1987) challenged the concept of a single dominant gene as proposed by Bale et al. (1986). Bale and Chakravarti (1987) defended their conclusion.
Traupe et al. (1989) also challenged the autosomal dominant hypothesis for dysplastic nevus syndrome on the basis of the lack of a genetic equilibrium between eliminated and newly arising mutations. Happle et al. (1982) had advanced arguments in favor of polygenic inheritance of dysplastic nevi: (1) lack of a consistent family pattern; (2) frequent sporadic occurrence of the trait; (3) continuous transition between ordinary and dysplastic nevi; and (4) analogy with an animal model.
Kraemer et al. (1983) found 4 persons affected with the dysplastic nevus phenotype. The risk of developing melanoma is not constant but increases with the number of melanoma patients in the family. This is a feature typical of polygenic inheritance.
Gilchrest et al. (1999) reviewed the role of ultraviolet radiation in the induction of melanoma. They pointed out that even among kindreds predisposed to multiple atypical melanocytic nevi and melanomas because of germline mutations in the CDKN2A gene (600160), retrospective analyses suggest that the incidence of melanoma has increased in recent generations, a phenomenon ascribed to the independent risk factor of increased sun exposure. Not only melanoma but also the more common skin cancers, basal cell and squamous cell carcinomas, are related to ultraviolet exposure. However, unlike the more common skin cancers, which are associated with total cumulative exposure to UV radiation, melanomas are associated with intense intermittent exposure. Thus, basal cell and squamous cell carcinomas occur most commonly in maximally sun-exposed areas of the body, such as the face and the backs of the hands and forearms, and in persons with almost daily and substantial lifetime exposure to UV radiation, such as farmers and sailors. In contrast, melanoma occurs most commonly in areas of the body exposed to the sun intermittently, such as the back in men and the lower legs in women, with relative sparing of more frequently exposed sites such as the face, hands, and forearms; it is most common in persons with predominantly indoor occupations whose exposure to the sun is limited to weekends and vacations. Indeed, the large increase in the incidence of melanoma in recent decades may be attributable to the ability of large numbers of people to travel long distances to obtain intense exposure to the sun in winter. The risk of melanoma is associated specifically with exposures that induce sunburn, and a history of 5 or more severe sunburns during adolescence more than doubles the risk. Gilchrest et al. (1999) suggested a biologic basis of these phenomena. The hypothesis was based on differences in response of keratinocytic stem cells and melanocytes to UV exposure. In melanocytes, a first high dose of ultraviolet radiation will cause substantial damage but not apoptosis; therefore, the melanocytes will survive to mutate and divide. Indeed, the appearance of freckles in children, often abruptly after high-dose sun exposure, is consistent with the thought that freckles represent clones of mutated melanocytes. In contrast, intermittent high-dose exposures to UV radiation result in loss of these cells, whereas repeated low-dose exposure would be expected ultimately to cause multiple mutations in the cells retained in the basal compartment and hence give rise to keratinocytic cancers.
Murine melanocytes ordinarily are confined to hair follicles. The skin of transgenic mice in which a metallothionein gene promoter forces the overexpression of hepatocyte growth factor/scatter factor (HGF/SF; 142409) has melanocytes in the dermis, epidermis, and dermal-ectodermal junction, and is thus more akin to human skin. Noonan et al. (2001) subjected albino HGF/SF transgenic mice and wildtype littermates to erythemal ultraviolet irradiation at 3.5 days of age, 6 weeks of age, or both. A single neonatal dose, which was 30-fold lower than the total ultraviolet dose administered previously to adult mice, was sufficient to induce melanoma in HGF/SF-transgenic mice after a relatively short latent period and with high cumulative incidence. This neonatal dose roughly corresponds to a sunburning dose of natural sunlight at midlatitudes in midsummer. Melanoma development in the transgenic mice after ultraviolet irradiation at both 3.5 days and 6 weeks was indistinguishable from that seen after only a single exposure at 3.5 days, whereas a similar dose at 6 weeks was not tumorigenic. However, the second exposure to ultraviolet light increased the multiplicity of melanocytic lesions as well as the incidence of nonmelanocytic tumors, including squamous cell carcinoma and sarcoma. Melanomas were not seen in either nontransgenic or untreated transgenic mice during the course of the experiment.
Curtin et al. (2005) demonstrated genetic diversity in melanomas related to susceptibility to ultraviolet light. They compared genomewide alternations in the number of copies of DNA and mutational status of BRAF (164757) and NRAS (164790) in 126 melanomas from 4 clinical groups in which the degree of exposure to ultraviolet light differed: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from arms, soles, and subungual (acral) sites; and 20 mucosal melanomas. They found significant differences in the frequencies of regional changes in the number of copies of DNA and mutational frequencies in BRAF among the 4 groups of melanomas. These samples could be correctly classified into the 4 groups with 70% accuracy on the basis of changes in the number of copies of genomic DNA. In 2-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84% accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89% accuracy. In 81% of melanomas on skin without chronic sun-induced damage, they found mutations in BRAF or NRAS; most melanomas in the other groups had mutations in neither gene. Melanomas with wildtype BRAF or NRAS frequently had increases in the number of copies of genes for cyclin-dependent kinase-4 (CDK4; 123829) and cyclin-1 (CCND1; 168461), which are downstream components of the RAS-BRAF pathway. In these studies, alterations in the number of copies of DNA was determined by comparative genomic hybridization.
Schatton et al. (2008) identified a subpopulation of tumor-initiating cells enriched for human malignant melanoma-initiating cells (MMIC) defined by expression of the chemoresistance mediator ABCB5 (611785) and showed that specific targeting of this tumorigenic minority population inhibits tumor growth. ABCB5-positive tumor cells detected in human melanoma patients showed a primitive molecular phenotype and correlated with clinical melanoma progression. In serial human-to-mouse xenotransplantation experiments, ABCBA5-positive melanoma cells possessed greater tumorigenic capacity than ABCB5-negative bulk populations and reestablished clinical tumor heterogeneity. In vivo genetic lineage tracking demonstrated a specific capacity of ABCB5-positive subpopulations for self-renewal and differentiation, because ABCB5-positive cancer cells generated both ABCB5-positive and ABCB5-negative progeny, whereas ABCB5-negative tumor populations gave rise, at lower rates, exclusively to ABCB5-null cells. In an initial proof-of-principle analysis designed to test the hypothesis that MMIC are also required for growth of established tumors, systemic administration of a monoclonal antibody directed at ABCB5, shown to be capable of inducing antibody-dependent cell-mediated cytotoxicity in ABCB5-positive MMIC, exerted tumor-inhibitory effects.
While studies on diverse cancers, including melanoma, in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice indicated that only rare human cancer cells (0.1-0.0001%) form tumors, the possibility that these studies underestimate the frequency of tumorigenic human cancer cells had been raised. Quintana et al. (2008) showed that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID mice (null for Il2rg, 308380), can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumors under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from 4 different patients formed tumors. Quintana et al. (2008) concluded that modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.
Passeron et al. (2009) found weak or absent SOX9 (608160) expression in 37 (95%) of 39 melanoma specimens. SOX9 expression was positive in normal skin areas, but weak or negative in 18 (81.8%) of 22 nevi, in 54 (96.4%) of 56 primary melanomas, and in 100% (20 of 20) metastatic melanomas. Thus, SOX9 expression decreased as melanocytic cells progressed from the normal condition to the premalignant (nevi) to the transformed state, and was completely negative in the most advanced (metastatic) state of malignancy. SOX9 functioned by binding the CDKN1A (116899) promoter, which resulted in strong suppression of cell growth in vivo. SOX9 also decreased PRAME (606021) protein levels in melanoma cells and restored sensitivity to retinoic acid. SOX9 overexpression in melanoma cell lines inhibited tumorigenicity both in mice and in a human ex vivo model of melanoma. Treatment of melanoma cell lines with PGD2 (176803) increased SOX9 expression and restored sensitivity to retinoic acid. Combined treatment with PGD2 and retinoic acid substantially decreased tumor growth in human ex vivo and mouse in vivo models of melanoma. These results provided insight into the pathophysiology of melanoma.
Kapoor et al. (2010) reported that the histone variant macroH2A (mH2A; 610054) suppresses tumor progression of malignant melanoma. Loss of mH2A isoforms, histone variants generally associated with condensed chromatin and fine-tuning of developmental gene expression programs, was positively correlated with increasing malignant phenotype of melanoma cells in culture and human tissue samples. Knockdown of mH2A isoforms in melanoma cells of low malignancy resulted in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms rescued these malignant phenotypes in vitro and in vivo. Kapoor et al. (2010) demonstrated that the tumor-promoting function of mH2A loss is mediated, at least in part, through direct transcriptional upregulation of CDK8 (603184). Suppression of CDK8, a colorectal cancer oncogene, inhibits proliferation of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferative advantage induced by mH2A loss. Moreover, a significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples. Kapoor et al. (2010) concluded that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma.
Zaidi et al. (2011) introduced a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. They used expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of IFN-gamma (147570), but not type I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2 (601267). Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-enhanced melanoma growth and survival. IFN-gamma-producing macrophages were also identified in 70% of human melanomas examined. Zaidi et al. (2011) concluded that their data revealed an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.
Ceol et al. (2011) used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) (164757.0001) and accelerate melanoma. SETDB1 (604396), an enzyme that methylates histone H3 (see 602810) on lysine-9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes (e.g., 142950), that are transcriptionally dysregulated in response to increased levels of SETDB1. Ceol et al. (2011) concluded that their studies established SETDB1 as an oncogene in melanoma and underscored the role of chromatin factors in regulating tumorigenesis.
White et al. (2011) used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (191170) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, White et al. (2011) performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH; 126064), e.g., leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. White et al. (2011) concluded that their studies, taken together, highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.
Straussman et al. (2012) developed a coculture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. They found that stroma-mediated resistance is common, particularly to targeted agents. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF; 142409) resulted in activation of the HGF receptor MET (164860), reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signaling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines.
Wilson et al. (2012) independently found that HGF confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells, and generalized that there is extensive redundancy of receptor tyrosine kinase (RTK)-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.
Johannessen et al. (2013) carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK (see 176872), ERK (see 601795), or combined RAF-MEK inhibitors. These studies revealed a cAMP-dependent melanocytic signaling network not previously associated with drug resistance that included G protein-coupled receptors, adenyl cyclase (ADCY9; 603302), protein kinase A (PRKACA; 601639), and CREB (123810). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS (164810), NR4A1 (139139), NR4A2 (601828), and MITF (156845). Combined treatment with MAPK pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Johannessen et al. (2013) concluded that these data suggested that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics.
Sun et al. (2014) found that 6 out of 16 BRAF(V600E) (164757.0001)-positive melanoma tumors analyzed acquired EGFR (131550) expression after the development of resistance to inhibitors of BRAF or MEK. Using a chromatin regulator-focused short hairpin RNA (shRNA) library, Sun et al. (2014) found that suppression of SRY-box 10 (SOX10; 602229) in melanoma causes activation of TGF-beta (190180) signaling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB; 173410), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells that have varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug treatment, but this is reversed when the treatment is discontinued. Sun et al. (2014) found evidence for SOX10 loss and/or activation of TGF-beta signaling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Sun et al. (2014) concluded that their findings provided a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identified patients with EGFR-positive melanoma as a group that may benefit from retreatment after a drug holiday.
To investigate how ultraviolet radiation (UVR) accelerates oncogenic BRAF-driven melanomagenesis, Viros et al. (2014) used a BRAF mutant (V600E) mouse model. In mice expressing the V600E mutation in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Viros et al. (2014) showed that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma but provided only partial protection. The UVR-exposed tumors showed increased numbers of single-nucleotide variants, and Viros et al. (2014) observed mutations in Trp53 (TP53; 191170) in approximately 40% of cases. TP53 is an accepted UVR target in human nonmelanoma skin cancer but was not thought to play a major role in melanoma. However, Viros et al. (2014) showed that in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that in humans TP53 mutations are linked to evidence of UVR-induced DNA damage in melanoma. Thus, the authors provided mechanistic insight into epidemiologic data linking UVR to acquired nevi in humans. Furthermore, they identified TP53/Trp53 as a UVR target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Viros et al. (2014) stated that their study validated public health campaigns that promote sunscreen protection for individuals at risk of melanoma.
Chiba et al. (2017) demonstrated that TERT (187270) promoter mutations acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TERT promoter mutations do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TERT promoter mutations requires a gradual upregulation of telomerase, coinciding with telomere fusions. These data suggested that TERT promoter mutations contribute to tumorigenesis by promoting immortalization and genomic instability in 2 phases. In an initial phase, TERT promoter mutations do not prevent bulk telomere shortening but extend cellular life span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further upregulated to sustain cell proliferation.
Metastasis
Bald et al. (2014) reported that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model created by Gaffal et al. (2011) promotes metastatic progression, independent of its tumor-initiating effects. UV irradiation enhanced the expansion of tumor cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box-1 (HMGB1; 163905) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor-4 (TLR4; 603030). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate toward endothelial cells and use selective motility cues on their surfaces. Bald et al. (2014) concluded that their results not only revealed how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also showed that the resulting inflammatory response catalyzes reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and hematogenous dissemination. Consistent with these findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases.
Luo et al. (2016) provided data indicating that PGC1-alpha (604517) suppresses melanoma metastasis, acting through a pathway distinct from that of its bioenergetic functions. Elevated PGC1-alpha expression inversely correlated with vertical growth in human melanoma specimens. PGC1-alpha silencing made poorly metastatic melanoma cells highly invasive and, conversely, PGC1-alpha reconstitution suppressed metastasis. Within populations of melanoma cells, there is a marked heterogeneity in PGC1-alpha levels, which predicts their inherent high or low metastatic capacity. Mechanistically, PGC1-alpha directly increases transcription of ID2 (600386), which in turn binds to and inactivates the transcription factor TCF4 (602272). Inactive TCF4 caused downregulation of metastasis-related genes, including integrins that influence invasion and metastasis. Inhibition of BRAFV600E (164757.0001) using vemurafenib, independently of its cytostatic effects, suppressed metastasis by acting on the PGC1-alpha-ID2-TCF4-integrin axis. Luo et al. (2016) concluded that PGC1-alpha maintains mitochondrial energetic metabolism and suppresses metastasis through direct regulation of parallel-acting transcriptional programs.
In 4 of 5 cases of malignant melanoma, Trent et al. (1983) found chromosome alterations, including deletion and translocation in the long arm of chromosome 6, specifically in the 6q15-q23 region. They pointed out that the MYB oncogene maps to this region. Becher et al. (1983), reviewing cytologic findings in malignant melanoma in their own and reported cases, likewise pointed to a high incidence of structural aberration of 6q (segment q11-q31), whereas the short arm remains structurally unchanged, though its genetic material is often duplicated, as in the case of isochromosome-6p in one of their cases. These findings accentuate the interest, they pointed out, in the relationships found between specific HLA haplotypes and familial malignant melanoma (Hawkins et al., 1981; Pellegris et al., 1982).
Pathak et al. (1983), Balaban et al. (1984), and Rey et al. (1985) also reported preferential abnormalities of chromosome 6. Hecht et al. (1989) found a marked increase in chromosomal rearrangements in dysplastic nevi from patients with CMM and in their normal-looking skin but not in their lymphocytes.
Linkage studies of a hypothetical dysplastic nevus (DN) locus and the cutaneous malignant melanoma (CMM) locus showed an association (lod = 3.857 at theta = 0.08). All families giving evidence on linkage were in coupling and the maximum likelihood estimate of recombination was not significantly different from 0 (Bale et al. (1985, 1986)). Bale et al. (1985) excluded linkage of CMM to HLA.
Multipoint linkage analysis appeared to support the assignment of CMM to 1p (Bale et al., 1987). In 3 Utah kindreds ascertained through multiple cases of melanoma, Cannon-Albright et al. (1990) could find no evidence of linkage with the 2 markers most closely linked in the Bale study. Both melanoma alone and a combined melanoma/dysplastic nevus syndrome phenotype were analyzed. Furthermore, multipoint linkage analysis excluded the CM/DNS locus from an area of 55 cM. Bale et al. (1989) presented further evidence supporting assignment of the CMM locus to chromosome 1p36, 7.6 cM distal to PND (108780) and flanked by D1S47.
Dracopoli et al. (1989) found loss of heterozygosity at loci on 1p in 43% of melanomas and 52% of melanoma cell lines. Analysis of multiple metastases derived from the same patient and of melanoma and lymphoblastoid samples from a family with hereditary melanoma showed that loss of heterozygosity at loci on distal 1p is a late event in tumor progression rather than the second mutation that would occur if melanoma were due to a cellular recessive mechanism. In neuroblastoma and in type II endocrine neoplasia also, 1p loss of heterozygosity is frequent, suggesting that this loss is a common late event of neuroectodermal tumor progression. By multipoint linkage analysis of 6 families, Dracopoli et al. (1989) found evidence that the familial melanoma gene maps to 1p36 about 8 cm distal to PND. The lod score was 5.42. Goldstein et al. (1993) extended the linkage studies to updated versions of these 6 families plus 7 new families. They concluded that there was 'significant evidence of heterogeneity,' and considered that this was responsible for the failure of some previous studies to confirm linkage to 1p in some families. Following up on previous linkage analyses of 19 cutaneous malignant melanoma/dysplastic nevi (CMM/DN) kindreds which showed significant evidence of linkage and heterogeneity to both chromosomes 1p and 9p (see CMM2; 155601), Goldstein et al. (1996) examined 2-locus hypotheses. The lod scores for CMM alone were highest using the single locus-heterogeneity model. They found much stronger evidence of linkage to 9p than to 1p for CMM alone; the lod scores were approximately 2 times greater on 9p than on 1p. A change in lod scores from an evaluation of CMM alone to CMM/DN suggested to the authors that a chromosome 1p locus contributed to both CMM and CMM/DN, whereas a 9p locus contributed more to CMM alone. For 2-locus models, the lod scores from 1p were greater for CMM/DN than for CMM alone. After conditioning on linkage to the other locus, only the 9p locus consistently showed significant evidence for linkage to CMM alone.
Falchi et al. (2009) conducted a genomewide association study for nevus (see 162900) count, which is a known risk factor for cutaneous melanoma, using 297,108 single-nucleotide polymorphisms (SNPs) in 1,524 twins, with validation in an independent cohort of 4,107 individuals. Falchi et al. (2009) identified strongly associated variants in the MTAP gene (156540), which is adjacent to the familial melanoma susceptibility locus CDKN2A on 9p21 (see 155601) (rs4636294, combined p = 3.4 x 10(-15)), as well as in the PLA2G6 gene (603604) on 22q13.1 (rs2284063, combined p = 3.4 x 10(-8)). Variants in these 2 loci also showed association with melanoma risk in 3,131 melanoma cases from 2 independent studies, including rs10757257 at 9p21 (combined p = 3.4 x 10(-8), odds ratio = 1.23) and rs132985 at 22q13.1 (combined p = 2.6 x 10(-7), odds ratio = 1.23).
Genetic Heterogeneity
Millikin et al. (1991) used RFLPs to look for loss of constitutional heterozygosity (LOH) for markers on 6q. LOH on chromosome 6q was identified in 21 of 53 informative loci (40%). The chromosomal region bearing the highest frequency of 6q allelic loss was defined by the marker loci MYB (189990) and ESR (133430) located at 6q22-q23 and 6q24-q27, respectively. Possibly contradictory to chromosome 6 information is the report of Greene et al. (1983) of possible linkage to Rh (which is on 1p). A maximum lod score of 2.0 at theta 0.30 was observed.
Nancarrow et al. (1992) reviewed the contradictory findings of linkage in this disorder and presented studies of 7 Australian kindreds. Both Cannon-Albright et al. (1990) and Kefford et al. (1991) had questioned the validity of dysplastic nevi as a marker for familial melanoma and excluded linkage to markers on 1p when familial melanoma alone (symbolized MLM) was used as the phenotype. Several of the Australian families studied by Kefford et al. (1991) showed little or no history of dysplastic nevus syndrome or surgical removal of histologically characterized dysplastic nevi. Of the 7 other Australian kindreds studied by Nancarrow et al. (1992), 3 had the largest number of affected individuals reported worldwide. Because they also had families without dysplastic nevi and because the data used to calculate the parameters of the model used by Kefford et al. (1991) were estimated from a population-based survey, Nancarrow et al. (1992) used the latter model but also analyzed the data with the model of Bale et al. (1989). The Kefford model was applied to MLM alone and took into account variable penetrance with age and variable frequency of sporadic cases with age. With this approach, they excluded MLM from a 40-cM region that spanned the interval between D1S47 and PND and extended approximately 15 cM on either side of these markers to a total of 70 cM. In addition, they excluded a region of about 20 cM around the D1S57/MYCL1 (164850) loci at 1p32. Nancarrow et al. (1992) carried out linkage analysis in 3 large Australian melanoma pedigrees, using 172 microsatellite markers spread across all autosomes. Three additional smaller families were typed for 70 of the same markers. In 5 of the 6 families, they found lod scores between 1.0 and 2.3, which suggested localization of melanoma genes in proximity to some of the markers. This may indicate genetic heterogeneity since there was no marker for which all families gave significantly high lods. Their data provided the basis of an exclusion map; regions of chromosome 6, 9cen, and 10qter could not be excluded in these studies.
Fung et al. (2003) described an online locus-specific variant database for familial melanoma.
Associations Pending Confirmation
In a Spanish case-control study of 131 consecutive melanoma patients and 245 controls, Fernandez et al. (2008) analyzed 23 SNPs in 6 candidate genes belonging to the pigmentation pathway. The only clear association was with the F374L variant in the SLC45A2 gene (606202.0008) on chromosome 5p13.3.
Following the identification of association of a SNP, rs401681, in an intron of the CLPTM1L gene (612585) on chromosome 5p15.33 with basal cell carcinoma (605462), Rafnar et al. (2009) tested rs401681 for association with 16 other cancer types in over 30,000 cancer cases and 45,000 controls. They found that rs401681 seems to confer protection against cutaneous melanoma (OR = 0.88, p = 8.0 x 10(-4)). The melanoma study included 2,381 patients and 30,839 controls. Most of the cancer types tested have a strong environmental component to their risk.
Bishop et al. (2009) identified and replicated 2 loci with strong evidence of association with risk for cutaneous melanoma: 16q24 encompassing MC1R (155555) (combined P = 2.54 x 10(27) for rs258322) and 11q14-q21 encompassing TYR (606933) (P = 2.41 x 10(-14) for rs1393350).
Somatic Mutations
By examining DNA copy number in 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.
Palavalli et al. (2009) performed mutation analysis of the matrix metalloproteinase (MMP) gene family in human melanoma and identified somatic mutations in 23% of melanomas. Five mutations in one of the most commonly mutated genes, MMP8 (120355), reduced MMP enzyme activity. Expression of wildtype but not mutant MMP8 in human melanoma cells inhibited growth on soft agar in vitro and tumor formation in vivo, suggesting that wildtype MMP8 has the ability to inhibit melanoma progression.
Prickett et al. (2009) performed a mutation analysis of the protein tyrosine kinase gene family in cutaneous metastatic melanoma. They identified 30 somatic mutations affecting the kinase domains of 19 protein tyrosine kinases and subsequently evaluated the entire coding regions of the genes encoding these 19 protein tyrosine kinases for somatic mutations in 79 melanoma samples. Prickett et al. (2009) found mutations in ERBB4 (600543) in 19% of individuals with melanoma and found mutations in 2 other kinases (FLT1, 165070 and PTK2B, 601212) in 10% of individuals with melanomas. Prickett et al. (2009) examined 7 missense mutations in ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib.
Pleasance et al. (2010) sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalog of somatic mutations from an individual cancer. Pleasance et al. (2010) suggested that the catalog provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas an uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions.
Using exome sequencing followed by screening of targeted genes in melanoma samples, Wei et al. (2011) found 34 distinct somatic mutations in the GRIN2A gene (138253) in 25.2% of 135 melanomas. These findings implicated the glutamate signaling pathway in the pathogenesis of melanoma. Somatic mutations were also found in the TRRAP gene (603015) in 6 (4%) of 167 melanoma samples, and in the DCC gene (120470) in 3 (2%) of 167 melanomas. The most common somatic mutation was V600E in the BRAF gene (164757.0001), which occurred in 65.4% of tumors.
Berger et al. (2012) sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per Mb of genome), intermediate in those originating from hair-bearing skin of the trunk (5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (612139), a PTEN (601728)-interacting protein and negative regulator of PTEN in breast cancer, as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo.
Prickett et al. (2011) used exon capture and massively parallel sequencing methods to analyze the mutational status of 734 G protein-coupled receptors in melanoma. This investigation revealed that one family member, GRM3 (601115), was frequently mutated and that 1 of its mutations was recurrent. Biochemical analysis of GRM3 alterations revealed that mutant GRM3 selectively regulated the phosphorylation of MAPK/ERK kinase (MEK; see 176872), leading to increased anchorage-independent growth and migration. Melanoma cells expressing mutant GRM3 had reduced cell growth and cellular migration after short hairpin RNA-mediated knockdown of GRM3 or treatment with a selective MEK inhibitor. Prickett et al. (2011) found that 16.3% of melanomas were affected with GRM3 mutations, making this gene the second most frequently mutated in their study; the most frequently mutated was GPR98 (602851), with a mutation rate of 27.5%. Prickett et al. (2011) found the GRM3 glu870-to-lys mutation in 4 different individuals with melanoma.
Nikolaev et al. (2012) performed exome sequencing to detect somatic mutations in protein-coding regions in 7 melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in 2 metastases derived from the same individual. Two melanomas with noncanonical BRAF mutations harbored gain-of-function MAP2K1 (MEK1; 176872) and MAP2K2 (MEK2; 601263) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%.
Stark et al. (2012) sequenced 8 melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, Stark et al. (2012) found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 (602448) or MAP3K9 (600136). Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggested that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W33X variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
Arafeh et al. (2015) analyzed 501 melanoma exomes and found that RASA2 (601589) was mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation and melanoma cell growth and migration. RASA2 expression was lost in at least 30% of human melanomas analyzed and was associated with reduced patient survival.
To identify driver genes for mucosal melanoma, Ablain et al. (2018) sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloging point mutations, amplifications, and deletions. The SPRED1 gene (609291), which encodes a negative regulator of mitogen-activated protein kinase (MAPK) signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, Ablain et al. (2018) found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT (164920) mutations. SPRED1 knockdown caused MAPK activation, increased cell proliferation, and conferred resistance to drugs inhibiting KIT tyrosine kinase activity.
Hayward et al. (2017) reported the analysis of whole genome sequences from cutaneous, acral, and mucosal subtypes of melanoma. The heavily mutated landscape of coding and noncoding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting noncoding sequences was similar to that affected by recurrent mutations in coding sequences. Significantly mutated genes included BRAF (164757), CDKN2A (600160), NRAS (164790) and TP53 (191170) in cutaneous melanoma, BRAF, NRAS and NF1 (613113) in acral melanoma, and SF3B1 (605590) in mucosal melanoma. Mutations affecting the TERT (187270) promoter were the most frequent of all; however, neither they nor ATRX (300032) mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the MAPK and phosphoinositol kinase (PIK) pathways.
Genetic Associations
Gudbjartsson et al. (2008) found association of a single-nucleotide polymorphism (SNP), rs1408799C, which had been associated with eye color (see SHEP11, 612271), with risk of cutaneous malignant melanoma (odds ratio = 1.15, p = 4.3 x 10(-4)).
The familial dysplastic nevus syndrome is a good example of a genetic disorder that lends itself to the practice of preventive genetics, i.e., preventive medicine, at the family level (Greene et al., 1985). Since 1960, mortality from cutaneous melanoma in the U.S. has risen more than mortality from any other cancer except carcinoma of the lung.
Interferon (IFN) alfa-2b (147562) is used to treat high-risk cutaneous melanomas, although IFN alfa therapy is associated with a number of systemic side effects, including a flu-like syndrome, fatigue, malaise, weight loss, depression, nausea, anorexia, diarrhea, neutropenia, and thrombocytopenia. Hejny et al. (2001) reported 7 patients who developed retinopathy while receiving high-dose IFN alfa-2b therapy for adjuvant treatment of high-risk cutaneous melanoma. The risk of retinopathy appeared to be greater with higher dosage therapy and caused severe vision loss in 2 patients. The authors concluded that patients receiving high-dose IFN alfa-2b therapy need to be monitored for sequelae, including retinal neovascularization, until the retinopathy has resolved.
Melanoma-associated retinopathy is a rare disorder characterized by metastatic melanoma, night blindness, and an electroretinographic pattern suggestive of congenital stationary night blindness (310500). Melanoma-associated retinopathy can be related to a variety of antiretinal antibodies. Potter et al. (2002) demonstrated the presence of antitransducin antibodies in the serum of a patient with a history of metastatic melanoma who had developed bilateral night blindness and decreased visual acuity. The authors postulated that recognition of transducin, a novel melanoma-associated retinopathy antigen, might be important for identifying and treating patients with night blindness and melanoma.
Flaherty et al. (2010) reported complete or partial regression of BRAF V600E (164757.0001)-associated metastatic melanoma in 81% of patients treated with an inhibitor (PLX4032) specific to the V600E mutation. Among 16 patients in a dose-escalation cohort, 10 had a partial response, and 1 had a complete response. Among 32 patients in an extension cohort, 24 had a partial response, and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Responses were observed at all sites of disease, including bone, liver, and small bowel. Tumor biopsy specimens from 7 patients showed markedly reduced levels of phosphorylated ERK, cyclin D1, and Ki67 (MKI67; 176741) at day 15 compared to baseline, indicating inhibition of the MAP kinase pathway.
Bollag et al. (2010) described the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic BRAF kinase activity. PLX4032 was cocrystallized with a protein construct that contained the kinase domain of BRAF(V600E). In a clinical trial, patients exposed to higher plasma levels of PLX4032 experienced tumor regression; in patients with tumor regressions, pathway analysis typically showed greater than 80% inhibition of cytoplasmic ERK phosphorylation. Bollag et al. (2010) concluded that their data demonstrated that BRAF-mutant melanomas are highly dependent on BRAF kinase activity.
Chapman et al. (2011) conducted a phase 3 randomized clinical trial comparing vemurafenib (PLX4032) with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation (164757.0001). Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1,000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. At 6 months, overall survival was 84% (95% CI, 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P less than 0.001 for both comparisons). After review of the interim analysis, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.
Thakur et al. (2013) investigated the cause and consequences of vemurafenib resistance using 2 independently-derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors showed continued dependency on BRAF(V600E) (164757.0001)-MEK-ERK signaling owing to elevated BRAF(V600E) expression. Thakur et al. (2013) showed that vemurafenib-resistant melanomas become drug-dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumors. Thakur et al. (2013) further demonstrated that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. Thakur et al. (2013) concluded that their data highlighted the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. These observations may contribute to sustaining the durability of vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.
Snyder et al. (2014) treated malignant melanoma exomes from 64 patients with CTLA4 (123890) blockade and then characterized the exomes using massively parallel sequencing. A discovery set consisted of 11 patients who derived long-term clinical benefit and 14 patients who derived either minimal or no benefit. Mutational load was associated with the degree of clinical benefit (p = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, Snyder et al. (2014) identified candidate tumor neoantigens for each patient. They elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA4 blockade. The authors validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. Snyder et al. (2014) concluded that these findings defined a genetic basis for benefit from CTLA4 blockade in melanoma and provided a rationale for examining exomes of patients for whom anti-CTLA4 agents are being considered. Chan et al. (2015) clarified their use of the term 'validation set' in this article (Snyder et al., 2014) and noted corrections made to the article online.
To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, Van Allen et al. (2015) analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, they also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, Van Allen et al. (2015) concluded that detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
Vetizou et al. (2015) found that the antitumor effects of CTLA4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA4 blockade.
Chen et al. (2018) reported that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PDL1 (605402) on their surface. Stimulation with interferon-gamma (IFNG; 147570) increased the amount of PDL1 on these vesicles, which suppressed the function of CD8 (see 186910) T cells and facilitates tumor growth. In patients with metastatic melanoma, the level of circulating exosomal PDL1 positively correlated with that of IFNG, and varied during the course of anti-PD1 (600244) therapy. The magnitudes of the increase in circulating exosomal PDL1 during early stages of treatment, as an indicator of the adaptive response of the tumor cells to T cell reinvigoration, stratified clinical responders from nonresponders. Chen et al. (2018) concluded that their study unveiled a mechanism by which tumor cells systemically suppress the immune system, and provided a rationale for the application of exosomal PDL1 as a predictor for anti-PD1 therapy.
To build a model of human melanoma, Dankort et al. (2009) generated mice with conditional melanocyte-specific expression of Braf(V600E) (164757.0001). Upon induction of Braf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15 to 20 months. By contrast, expression of Braf(V600E) combined with Pten (601728) tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency, and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (see 601231) or Mek1/2 (see 176872) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with both drug inhibitors led to shrinkage of established melanomas.
The earliest report of familial CMM may be that of Norris (1820). In describing a case of malignant melanoma, Norris wrote: 'It is remarkable that this gentleman's father, about thirty years ago, died of a similar disease. A surgeon of this town attended him, and he informed me that a number of small tumours appeared between the shoulders...This tumour, I have remarked, originated in a mole, and it is worth mentioning, that not only my patient and his children had many moles on various parts of their bodies, but also his own father and brothers had many of them. The youngest son had one of these marks exactly in the same place where the disease in his father first manifested itself. These facts, together with a case that has come under my notice, rather similar, would incline me to believe that this disease is hereditary.' See commentary by Hecht (1989).
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