ORPHA: 618; DO: 8923;
Cytogenetic location: 1p22 Genomic coordinates (GRCh38): 1:84,400,001-94,300,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p22 | {Melanoma, cutaneous malignant, 4} | 608035 | 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).
For a discussion of genetic heterogeneity of cutaneous malignant melanoma (CMM), see 155600.
It is estimated that 10% of CMM cases have an inherited predisposition. Although mutations in 2 genes, CDKN2A (600160) and CDK4 (123829), confer an increased risk of CMM, they account for only 20 to 25% of families with multiple cases of CMM. To localize additional loci involved in CMM susceptibility, Gillanders et al. (2003) performed a genomewide scan for linkage in 49 Australian pedigrees containing at least 3 CMM cases in which CDKN2A and CDK4 involvement had been excluded. The highest 2-point parametric lod score, 1.82 at theta of 0.2, was obtained at D1S2726, which maps to chromosome 1p22. A parametric lod score of 4.65 at theta of 0.0 and a nonparametric lod score of 4.19 were found at D1S2779 in 9 families selected for early age of onset. Additional typing yielded 7 adjacent markers with lod scores greater than 3 in this subset. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. The highest lod score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest stages of onset were included. Gillanders et al. (2003) concluded that a novel CMM susceptibility locus, designated CMM4, is located at chromosome 1p22.
Critical recombinants in linked families studied by Gillanders et al. (2003) localized the CMM4 locus to a 15-Mb region between D1S430 and D1S2664. To map the locus more finely, Walker et al. (2004) performed studies to assess allelic loss across the region in a panel of melanomas from 1p22-linked families, sporadic melanomas, and melanoma cell lines. In 80% of familial melanomas they found loss of heterozygosity (LOH) within the region, with the smallest region of overlapping deletions (SRO) between D1S207 and D1S435, a region of approximately 9 Mb. From this high frequency of LOH, Walker et al. (2004) concluded that the susceptibility locus is a tumor suppressor.
Gillanders, E., Juo, S.-H. H., Holland, E. A., Jones, M., Nancarrow, D., Freas-Lutz, D., Sood, R., Park, N., Faruque, M., Markey, C., Kefford, R. F., Palmer, J., and 15 others. Localization of a novel melanoma susceptibility locus to 1p22. Am. J. Hum. Genet. 73: 301-313, 2003. [PubMed: 12844286] [Full Text: https://doi.org/10.1086/377140]
Habif, T. P. Clinical Dermatology (5th ed.) St. Louis: Mosby/Elsevier (pub.) 2010.
Walker, G. J., Indsto, J. O., Sood, R., Faruque, M. U., Hu, P., Pollock, P. M., Duray, P., Holland, E. A., Brown, K., Kefford, R. F., Trent, J. M., Mann, G. J., Hayward, N. K. Deletion mapping suggests that the 1p22 melanoma susceptibility gene is a tumor suppressor localized to a 9-Mb interval. Genes Chromosomes Cancer 41: 56-64, 2004. [PubMed: 15236317] [Full Text: https://doi.org/10.1002/gcc.20056]