FaCD Online Syndrome Fact Sheet

Last updated: 25 Apr 2013

Name: Melanoma, Familial Clustering of

Mode of Inheritance: multifact?

Genes

GSTM1, mapped to 1p13.3
HLA-A, mapped to 6p21.3
HLA-B, mapped to 6p21.3
HLA-DQB1, mapped to 6p21.3
MC1R, mapped to 16q24.3
TERT, mapped to 5p15.33

Tumor features

melanoma, cutaneous

Comment

Approximately 5-10 % of melanoma cases are familial and a family history of melanoma is a well known risk factor for the development of this tumor[1;2] and for this reason some authors suggest performing initial screening in first-degree relatives of all patients with melanoma[3]. Some of the other known risk factors, as for example pigment traits, have a genetic background and this may also be true for the number of melanocytic nevi[1;4;5]. These risk factors may contribute to melanoma clustering in families[2;6]. However, the study by Ford et al.[7] failed to show a relationship between family history of melanoma and number of nevi, pigment traits and freckling, suggesting an independent shared (inherited ?) risk factor. First-degree relatives of melanoma patients have a relative risk (RR) of approximately 2 to develop this tumor[7-9] and this is even higher in first-degree relatives of cases diagnosed before the age of 50 (RR 6.5)[8].

Hereditary melanoma associated with germline CDKN2A and CDK4 mutations is discussed in another file. Deficiency of glutathione S-transferase Mu has been associated with increased risk to melanoma (RR 2)[10], although this has been questioned by another study[11]. A polymorphism of HLA class I is also associated with melanoma susceptibility[12]. Bateman et al.[13] found that HLA-DQB1 alleles *0303 and *0301 were positively associated with cutaneous malignant melanoma in a British cohort of patients. Interestingly Lulli et al.[14] found the exact opposite in an Italian population. In a segregation analysis of cutaneous melanoma in Australia (Queensland), by Aitken et al.[15], both Mendelian inheritance of a single major gene and purely environmental transmission were rejected. There was clear evidence of a, probably heterogeneous, familial risk factor. Germline variants in MC1R are strongly associated with BRAF mutations in non-CSD (chronic suninduced damage) melanomas. In this tumor subtype, the risk for melanoma associated with MC1R is due to an increase in risk of developing melanomas with BRAF mutations[16].

References

[1] Liu TP, Soong SJ. Epidemiology of malignant melanoma. Surg Clin North Am 76[6], 1205. 1996.
[2] Grange F, Chompret A, Guilloudbataille M, Guillaume JC, Margulis A, Prade M, Demenais F, Avril MF. Comparison between familial and nonfamilial melanoma in France. Arch Dermatol 1995; 131:1154-1159.
[3] NIH Consensus Conference. Diagnosis and treatment of early melanoma. JAMA 1992; 268(10):1314-1319.
[4] Briollais L, Chompret A, Guilloud-Bataille M, Feingold N, Avril MF, Demenais F. Genetic and epidemiological risk factors for a malignant melanoma- predisposing phenotype: The great number of nevi. Genet Epidemiol 13[4], 385-402. 1996.
[5] Breitbart M, Metneki J, Weichenthal M, Thrane J, Beres J, Rott HD, Breitbart EW. A study of Hungarian twins involving the influence of genetic and environmental factors on benign, melanocytic lesions. Eur J Dermatol 6[8], 548-551. 1996.
[6] Aitken JF, Duffy DL, Green A, Youl P, Maclennan R, Martin NG. Heterogeneity of melanoma risk in families of melanoma patients. Am J Epidemiol 1994; 140:961-973.
[7] Ford D, Bliss JM, Swerdlow AJ, Armstrong BK, Franceschi S, Green A, Holly EA, Mack T, Mackie RM, Osterlind A, Walter SD, Peto J, Easton DF. Risk of cutaneous melanoma associated with a family history of the disease. The International Melanoma Analysis Group (IMAGE). Int J Cancer 1995; 62(4):377-381.
[8] Goldgar DE, Easton DF, Cannon Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first- degree relatives of cancer probands. J Natl Cancer Inst 1994; 86(21):1600-1608.
[9] Cannon-Albright LA, Kamb A, Skolnick M. A review of inherited predisposition to melanoma. Semin Oncol 23[6], 667-672. 1996.
[10] Lafuente A, Molina R, Palou J, Castel T, Moral A, Trias M. Phenotype of glutathione S-transferase Mu (GSTM1) and susceptibility to malignant melanoma. Br J Cancer 1995; 72:324-326.
[11] Shanley SM, Chenevixtrench G, Palmer J, Hayward N. Glutathione S-transferase GSTM1 null genotype is not overrepresented in Australian patients with nevoid basal cell carcinoma syndrome or sporadic melanoma. Carcinogenesis 1995; 16:2003-2004.
[12] Muto M, Ohmura A, Nakano J, Yamazaki N, Yamamoto A, Ishihara K, Sasazuki T, Asagami C. HLA class I polymorphism and the susceptibility to malignant melanoma. Tissue Antigens 47[5], 447-449. 1996.
[13] Bateman AC, Turner SJ, Theaker JM, Howell WM. HLA-DQB1*0303 and *0301 alleles influence susceptibility to and prognosis in cutaneous malignant melanoma in the British Caucasian population. Tissue Antigens 52[1], 67-73. 1998.
[14] Lulli P, Grammatico P, Brioli G, Catricala C, Morellini M, Roccella M, Mariani B, Pennesi G, Roccella F, Cappellacci S, Trabace S. HLA-DR and -DQ alleles in Italian patients with melanoma. Tissue Antigens 51[3], 276-280. 1998.
[15] Aitken JF, Bailey-Wilson J, Green AC, Maclennan R, Martin NG. Segregation analysis of cutaneous melanoma in Queensland. Genet Epidemiol 15[4], 391-401. 1998.
[16] Landi MT, Bauer J, Pfeiffer RM, Elder DE, Hulley B, Minghetti P, Calista D, Kanetsky PA, Pinkel D, Bastian BC. MC1R germline variants confer risk for BRAF-mutant melanoma. Science (New York, N.Y.) 2006; 313(5786):521-2.