Abstract
SUMMARY
The genetic risk factors for melanoma are complex and involve both familial and environmental components. Of the thousands of melanomas diagnosed each year, only a fraction are due to familial causes. These melanomas typically present in younger individuals, and may be associated with genetic factors that put these individuals at risk for other tumors. CDKN2A and CDK4 are the most well-characterized mutations, as they have been identified in up to 40% of familial melanomas. Individuals with CDKN2A are also at risk for pancreatic cancer. The BRCA2 mutation has also been implicated in familial melanomas, breast and ovarian cancer. The BAP1, TERC and POT1 mutations are associated with melanomas and several other familial tumors.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . The characterization and potential impact of melanoma cases with unknown thickness in the United States’ Surveillance, Epidemiology, and End Results Program, 1989–2008. Cancer Epidemiol. 37(1), 64–70 (2013).
- 2 . Melanoma incidence and mortality in Europe: new estimates, persistent disparities. Br. J. Dermatol. 167(5), 1124–1130 (2012).
- 3 . Incidence, mortality and survival in cutaneous melanoma. J. Plast. Reconstr. Aesthet. Surg. 60(1), 32–40 (2007).
- 4 SEER Cancer Statistics Review, 1975–2011. National Cancer Institute, Bethesda, MD, USA. http://seer.cancer.gov/csr/1975_2011/.
- 5 . Genetic risk factors for melanoma. Hum. Genet. 126(4), 499–510 (2009).
- 6 . Melanoma susceptibility genes and risk assessment. Methods Mol. Biol. 1102, 381–393 (2014).•• This is a good review article about the molecular pathways and pathogenesis of genes implicated in melanoma and associated tumors.
- 7 . The genetics of susceptibility to cutaneous melanoma. Drugs Today (Barcelona). 41(3), 193–203 (2005).
- 8 . High- and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev. Anticancer Ther. 6(5), 657–670 (2006).
- 9 . Driver mutations in melanoma: lessons learned from bench-to-bedside studies. Curr. Oncol. Rep. 14(5), 449–457, 2012.
- 10 UV light accelerates melanoma metastasis. Cancer Discov. 4(6), 625–626 (2014).
- 11 . Primary malignant melanoma of the vulva – an aggressive tumor for modeling the genesis of non-UV light-associated melanomas. Acta Oncol. 43(5), 421–435 (2004).
- 12 . Germline melanoma susceptibility and prognostic genes: a review of the literature. J. Am. Acad. Dermatol. 67(5), 1055–1067 (2012).
- 13 Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J. Med. Genet. 44(2), 99–106 (2007).• Provides an overview of the epidemiology of CDKN2A, and reviews tumors associated with this gene mutation.
- 14 Population-based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas. Genes Chromosomes Cancer 47(2), 175–184 (2008).
- 15 . CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas. Cancer Res. 60(24), 6864–6867 (2000).
- 16 . Management of familial melanoma. Lancet Oncol. 8(1), 46–54 (2007).
- 17 Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non-melanoma skin cancer. Oncotarget 5(6), 1439–1451 (2014).
- 18 . The genetics of melanoma: recent advances. Annu. Rev. Genomics Hum. Genet. 14, 257–279 (2013).
- 19 Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J. Natl Cancer Inst. 102(20), 1568–1583 (2010).
- 20 Geographical variation in the penetrance of CDKN2A mutations for melanoma. J. Natl Cancer Inst. 94(12), 894–903 (2012).
- 21 . Genetic epidemiology of melanoma: of consortia and conundrums. J. Natl Cancer Inst. 94(12), 872–873 (2002).
- 22 Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study. JAMA Dermatol. 150(8), 819–827 (2014).
- 23 Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations. J. Invest. Dermatol. 114(1), 28–33 (2000).
- 24 Familial melanoma: clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family. J. Am. Acad. Dermatol. 67(6), 1257–1264 (2012).
- 25 Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 94(1), 84–96 (2002).
- 26 High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families. J. Med. Genet. 51(8), 545–552 (2014).
- 27 Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. J. Am. Acad. Dermatol. 71(5), 888–895 (2014).
- 28 . The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin. Cancer Res. 19(19), 5320–5328 (2013).
- 29 Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J. Med. Genet. 50(4), 264–270 (2013).• Reviews phenotypic findings and associations based on the 17 families known to have a CDK4 mutation.
- 30 Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat. Genet. 12(1), 97–99 (1996).
- 31 CDKN2A and CDK4 variants in Latvian melanoma patients: analysis of a clinic-based population. Melanoma Res. 17(3), 185–191 (2007).
- 32 Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam. Cancer 11(2), 235–242 (2012).
- 33 Potential excess mortality in BRCA1/2 mutation carriers beyond breast, ovarian, prostate, and pancreatic cancers, and melanoma. PLoS ONE 4(3), e4812 (2009).
- 34 BRCA2 mutations in a population-based series of patients with ocular melanoma. Int. J. Cancer 102(2), 188–191 (2002).
- 35 . Cancer risks among BRCA1 and BRCA2 mutation carriers. Br. J. Cancer 96(1), 11–15 (2007).• Provides a concise review of tumors associated with both BRCA1 and BRCA2 genes.
- 36 . Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91(15), 1310–1316 (1999).
- 37 . Germline mutations in BAP1 impair its function in DNA double-strand break repair. Cancer Res. 74(16), 4282–4294 (2014).
- 38 Germline mutations in BAP1 predispose to melanocytic tumors. Nat. Genet. 43(10), 1018–1021 (2011).
- 39 Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J. Med. Genet. 48(12), 856–859 (2011).
- 40 Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS ONE 7(4), e35295 (2012).
- 41 Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330(6009), 1410–1413 (2010).•• Documents the association of BAP1 mutations with uveal melanoma. Provides a detailed discussion on how BAP1 was elucidating from families with uveal melanoma.
- 42 . Tumours associated with BAP1 mutations. Pathology 45(2), 116–126 (2013).
- 43 BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J. Transl. Med. 10, 179 (2012).
- 44 A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers. PLoS ONE 8(8), e72144 (2013).
- 45 Germline BAP1 mutations predispose also to multiple basal cell carcinomas. Clin. Genet.
doi:10.1111/cge.12472. (2014) (Epub ahead of print). - 46 Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 43(10), 1022–1025 (2011).
- 47 Toward an improved definition of the tumor spectrum associated with BAP1 germline mutations. J. Clin. Oncol. 30(32), e337–e340 (2012).
- 48 TERT promoter mutations in familial and sporadic melanoma. Science 339(6122), 959–961 (2013).•• Discusses the TERT mutation and its association with melanoma and other tumors.
- 49 . Highly recurrent TERT promoter mutations in human melanoma. Science 339(6122), 957–959 (2013).•• Discusses the TERT mutation and its association with melanoma and other tumors.
- 50 TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. PLoS ONE 8(11), e80354 (2013).
- 51 . Variation at the TERT locus and predisposition for cancer. Expert Rev. Mol. Med. 12, e16 (2010).
- 52 Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat. Genet. 45(4), 371–384, 384e1–2 (2013).
- 53 TERT promoter mutations in skin cancer: the effects of sun exposure and X-irradiation. J. Invest. Dermatol. 134(8), 2251–2257 (2014).
- 54 Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat. Genet. 46(5), 482–486 (2014).•• Discusses the TERT mutation and its association with melanoma and other tumors.
- 55 POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. 46(5), 478–481 (2014).•• Discusses the TERT mutation and its association with melanoma and other tumors.
- 56 POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat. Genet. 45(5), 526–530 (2013).
- 57 . Cancer chromosomes going to POT1. Nat. Genet. 45(5), 473–475 (2013).
- 58 Telomeres and chromosomal instability in chronic lymphocytic leukemia. Leukemia 27(2), 490–493 (2013).