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HGNC Approved Gene Symbol: ROS1
Cytogenetic location: 6q22.1 Genomic coordinates (GRCh38): 6:117,287,353-117,425,942 (from NCBI)
ROS1, the human homolog of the transforming gene v-ros of the avian sarcoma virus UR2, encodes a protein tyrosine kinase receptor.
Using an assay for human protooncogenes based on the tumorigenicity of mouse NIH 3T3 cells cotransfected with DNA from a human mammary carcinoma cell line, Birchmeier et al. (1986) identified an activated ROS1 gene, which they called MCF3. ROS1 encodes a protein tyrosine kinase with a potential transmembrane domain. It arose from the human ROS1 gene by a rearrangement introduced during gene transfer, which deleted the putative extracellular domain of ROS1, leaving potential transmembrane and intracellular protein tyrosine kinase domains intact.
In a survey of 45 different human cell lines, Birchmeier et al. (1987) found ROS1 to be expressed in glioblastoma-derived cell lines at high levels and not to be expressed at all, or expressed at very low levels, in the remaining cell lines. The ROS1 gene was present in normal copy numbers in all cell lines that expressed the gene. However, in 1 particular glioblastoma line, Birchmeier et al. (1987) detected a potential activating mutation at the ROS1 locus.
Birchmeier et al. (1990) cloned a full-length human ROS1 cDNA from a glioblastoma cell line. ROS1 encodes a 2,347-amino acid protein with a predicted molecular mass of 259 kD. It contains an intracellular domain typical of tyrosine protein kinases, a transmembrane domain, a very large extracellular domain that contains 31 potential N-linked glycosylation sites, and a putative N-terminal signal peptide. The sequence of its extracellular domain shows homology with that of the Drosophila sevenless gene. Birchmeier et al. (1990) identified an 8.3-kb transcript of the ROS1 gene in glioblastoma cell lines but not in a primary glial cell line or in adult brain tissue.
Charest et al. (2003) reported the analysis of an interstitial deletion of 240 kb on 6q21 that fused the FIG gene (606845) to the ROS1 gene in glioblastoma cell lines. The resulting ROS1/FIG fusion protein is a constitutively activated tyrosine kinase. This was the first example of a genomic event that leads to the formation of a receptor tyrosine kinase (RTK) fusion protein in an astrocytoma.
Using a genomic clone, Nagarajan et al. (1986) mapped the ROS oncogene to 6q16-q22 by Southern analysis of DNA from hybrid cells and by in situ hybridization. They suggested that ROS joins MYB (189990), which is situated more distally on 6q, as a candidate for involvement in 6q deletions and rearrangements seen in various malignancies.
Yoshida et al. (1987) assigned the ROS gene to 6q22 by a combination of studies in somatic cell hybrids and in situ hybridization.
By in situ hybridization with a fragment of the MCF3 gene from placenta, Rabin et al. (1985) mapped MCF3 to 6q16-q22. Rabin et al. (1987) localized ROS1 to 6q16-q22 by in situ hybridization.
Satoh et al. (1987) mapped ROS1 to 6q22 by in situ hybridization. Chromosomal rearrangements in the 6q11-q31 region have been observed in acute lymphoblastic leukemia, malignant melanoma, and ovarian carcinoma.
Family history is a major risk factor for myocardial infarction (MI). Shiffman et al. (2005) hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. They analyzed more than 11,000 SNPs in almost 7,000 genes in 3 sequential studies involving a total of 1,332 Caucasian MI patients and 1,772 controls. They found 4 gene variants associated with MI (p less than 0.05; false-discovery rate less than 10%): palladin (608092) (odds ratio = 1.40); a tyrosine kinase, ROS1 (165020) (OR = 1.75); and 2 G protein-coupled receptors, TAS2R50 (609627) (OR = 1.58), and OR13G1 (611677) (OR = 1.40). The odds ratios cited were for carriers of 2 versus 0 risk alleles.
Birchmeier, C., Birnbaum, D., Waitches, G., Fasano, O., Wigler, M. Characterization of an activated human ROS gene. Molec. Cell. Biol. 6: 3109-3116, 1986. [PubMed: 3785223] [Full Text: https://doi.org/10.1128/mcb.6.9.3109-3116.1986]
Birchmeier, C., O'Neill, K., Riggs, M., Wigler, M. Characterization of ROS1 cDNA from a human glioblastoma cell line. Proc. Nat. Acad. Sci. 87: 4799-4803, 1990. [PubMed: 2352949] [Full Text: https://doi.org/10.1073/pnas.87.12.4799]
Birchmeier, C., Sharma, S., Wigler, M. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc. Nat. Acad. Sci. 84: 9270-9274, 1987. [PubMed: 2827175] [Full Text: https://doi.org/10.1073/pnas.84.24.9270]
Charest, A., Lane, K., McMahon, K., Park, J., Preisinger, E., Conroy, H., Housman, D. Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21). Genes Chromosomes Cancer 37: 58-71, 2003. [PubMed: 12661006] [Full Text: https://doi.org/10.1002/gcc.10207]
Nagarajan, L., Louie, E., Tsujimoto, Y., Balduzzi, P. C., Huebner, K., Croce, C. M. The human c-ros gene (ROS) is located at chromosome region 6q16-6q22. Proc. Nat. Acad. Sci. 83: 6568-6572, 1986. [PubMed: 3529088] [Full Text: https://doi.org/10.1073/pnas.83.17.6568]
Rabin, M., Birnbaum, D., Wigler, M., Ruddle, F. H. MCF3 oncogene mapped to region on chromosome 6 associated with malignant transformation. (Abstract) Am. J. Hum. Genet. 37: A36 only, 1985.
Rabin, M., Birnbaum, D., Young, D., Birchmeier, C., Wigler, M., Ruddle, F. H. Human ROS1 and MAS1 oncogenes located in regions of chromosome 6 associated with tumor-specific rearrangements. Oncogene Res. 1: 169-178, 1987. [PubMed: 3329713]
Satoh, H., Yoshida, M. C., Matsushime, H., Shibuya, M., Sasaki, M. Regional localization of the human c-ros-1 on 6q22 and flt on 13q12. Jpn. J. Cancer Res. 78: 772-775, 1987. [PubMed: 3115921]
Shiffman, D., Ellis, S. G., Rowland, C. M., Malloy, M. J., Luke, M. M., Iakoubova, O. A., Pullinger, C. R., Cassano, J., Aouizerat, B. E., Fenwick, R. G., Reitz, R. E., Catanese, J. J., Leong, D. U., Zellner, C., Sninsky, J. J., Topol, E. J., Devlin, J. J., Kane, J. P. Identification of four gene variants associated with myocardial infarction. Am. J. Hum. Genet. 77: 596-605, 2005. [PubMed: 16175505] [Full Text: https://doi.org/10.1086/491674]
Yoshida, M. C., Satoh, H., Matsushime, H., Shibuya, M., Sasaki, M. Two ros-related protooncogenes, c-ros-1 and flt, are regionally mapped on human chromosomes 6q22 and 13q12, respectively. (Abstract) Cytogenet. Cell Genet. 46: 724 only, 1987.