FaCD Online Syndrome Fact Sheet

Last updated: 02 May 2013

Name: Hereditary Melanoma

Synonym: Familial Atypical Multiple Mole Melanoma sydrome, FAMMM, Familial Dysplastic Nevus syndrome

Mode of Inheritance: AD

Genes

CDK4, mapped to 12q14
CDKN2A/p14(ARF), mapped to 9p21
CDKN2A/p16(INK4), mapped to 9p21
CMM1#, mapped to 1p36

Tumor features

melanoma, cutaneous
melanoma, uveal (choroidal, ciliary body, iris)/ocular
pancreatic adenocarcinoma

Tumor features (possible)

breast cancer
multiple myeloma (Kahler's disease)
neurofibroma of the skin
neurofibroma, general
non-seminoma
seminoma
tongue cancer

Non-tumor features

dysplastic/atypical nevi

Comment

Melanoma and multiple atypical nevi are characteristic findings in hereditary melanoma, in the past referred to as Familial Atypical Multiple Mole Melanoma syndrome (FAMMM) or familial dysplastic nevus syndrome, an autosomal dominant disorder which is genetically heterogeneous[1-4]. Although dysplastic nevi and melanomas have been reported to cluster within the same families and patients[5], hereditary melanoma may occur in the absence of dysplastic nevi. Including dysplastic nevi as an indicator for hereditary melanoma has confused genetic analysis[4;6;7].

Uveal melanomas have been reported to occur in patients with hereditary melanoma and sporadic dysplastic nevus syndrome[8]. In addition to melanomas, other tumors may belong to the hereditary melanoma tumor spectrum. Pancreatic cancer is the most prominent of them[9], typically associated with the p-16 Leiden CDKN2A mutation. Vasen et al.[10] estimated the cumulative risk for pancreatic cancer in p16-Leiden families to be 17% by age 75. Possibly, testicular germ cell tumors belong to the spectrum as well[11]. In Swedish families with a germline 113insArg mutation of the CDKN2A gene, a more than expected occurrence of breast cancer was observed[12]. Still, germline CDKN2A mutations appear to be infrequent in female patients with melanoma and breast cancer and mutations in BRCA1 or BRCA2 or in TP53 should be considered as well[24,25]. In a patient with multiple myeloma from a CDKN2A-associated melanoma family, loss of the wild type CDKN2A allele was observed in the malignant plasma cells, suggesting that the CDKN2A mutation contributed to the development of the multiple myeloma in this patient[13]. A similar situation was observed for a patient with multiple tongue cancers and a germline CDKN2A/INK4A mutation[23]. See also Familial Malignant Melanoma and Tumors of the Nervous System for a particular genotype associated with melanoma as well as nervous system tumors. It has been suggested that neurofibromas are part of FAMMM[26].

Cumulative risks to develop melanomas in hereditary melanoma gene carriers have been estimated at approximately 50 % at age 80[14] and 20 to 70 % at age 40 depending on the birth cohort, with gene carriers born after 1940 having the highest risk [15], although these latter calculations have been questioned[16]. There is geographical variation in the penetrance of CDKN2A mutations. One study estimated penetrance by age 50 years of 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia, and by age 80 years 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia[17].
Similar to what has been observed for some other tumor syndromes including BRCA1/2 type hereditary breast cancer and Lynch syndrome, CDKN2A mutation carriers in the general population appear to have have a much lower risk of melanoma than that suggested by estimates obtained from multiple-case families. Bigg et al estimated the risk of melanoma in CDKN2A mutation carriers at approximately 14% (95% CI = 8% to 22%) by age 50 years, 24% (95% CI = 15% to 34%) by age 70 years, and 28% (95% CI = 18% to 40%) by age 80 years[18].

Predicting the chance of finding a CDKN2a mutation in a family/individual depends on family history (number of affected relatives, ages at diagnosis, occurrence of pancreatic cancer and multiple primary melanomas)[19]. Software has been developed to assist with these predictions[20]. The predictive strength of mentioned phenotypical features show geographical variation[21], the most striking being the lack of a pancreatic cancer-CDKN2A mutation association in Australia.

Links

Melanoma Genetics Consortium - GenoMEL 18 1 08

References

[1] Lynch HT, Fusaro RM, Danes BS, Kimberling WJ, Lynch JF. A review of hereditary malignant melanoma including biomarkers in familial atypical multiple mole melanoma syndrome. Cancer Genet Cytogenet 1983; 8:325-358.
[2] Bergman W, Gruis NA, Sandkuijl LA, Frants RR. Genetics of seven Dutch familial atypical multiple mole melanoma syndrome families: A review of linkage results including chromosomes 1 and 9. J Invest Dermatol 1994; 103:S122-S125.
[3] Walker GJ, Nancarrow DJ, Walters MK, Palmer JM, Weber JL, Hayward NK. Linkage analysis in familial melanoma kindreds to markers on chromosome 6p. Int J Cancer 1994; 59:771-775.
[4] Cannon-Albright LA, Kamb A, Skolnick M. A review of inherited predisposition to melanoma. Semin Oncol 23[6], 667-672. 1996.
[5] Novakovic B, Clark WH, Fears TR, Fraser MC, Tucker MA. Melanocytic nevi, dysplastic nevi, and malignant melanoma in children from melanoma-prone families. J Am Acad Dermatol 1995; 33:631-636.
[6] Hussussian CJ, Struewing JP, Goldstein AM, Higgins PAT, Ally DS, Sheahan MD, Clark WH, Tucker MA, Dracopoli NC. Germline p16 mutations in familial melanoma. Nat Genet 1994; 8:15-21.
[7] Puig S, Ruiz A, Castel T, Volpini V, Malvehy J, Cardellach F, Lynch M, Mascaro JM, Estivill X. Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene. Hum Genet 101[3], 359-364. 1997.
[8] Van Hees CLM, Jager MJ, Bleeker JC, Kemme H, Bergman W. Occurrence of cutaneous and uveal melanoma in patients with uveal melanoma and their first degree relatives. Melanoma Res 8[2], 175-180. 1998.
[9] Lal G, Liu L, Hogg D, Lassam NJ, Redston MS, Gallinger S. Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Gene Chrom Cancer 2000; 27:358-361.
[10] Vasen HFA, Gruis NA, Frants RR, van der Velden PA, Hille ETM, Bergman W. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000; 87(6):809-811.
[11] Sigg C, Pelloni F. Dysplastic nevi and germ cell tumors of the testis-a possible further tumor in the spectrum of associated malignancies in dysplastic nevus syndrome. Dermatologica 1988; 176:109-110.
[12] Borg A, Sandberg T, Nilsson K, Johannsson O, Klinker M, Masback A, Westerdahl J, Olsson H, Ingvar C. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000; 92(15):1260-1266.
[13] Dilworth D, Liu L, Stewart AK, Berenson JR, Lassam N, Hogg D. Germline CDKN2A mutation implicated in predisposition to multiple myeloma. Blood 2000; 95(5):1869-1871.
[14] Cannon-Albright LA, Meyer LJ, Goldgar DE, Lewis CM, Mcwhorter WP, Jost M, Harrison D, Anderson DE, Zone JJ, Skolnick MH. Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM). Cancer Res 1994; 54:6041-6044.
[15] Battistutta D, Palmer J, Walters M, Walker G, Nancarrow D, Hayward N. Incidence of familial melanoma and MLM2 gene. Lancet 1994; 344:1607-1608.
[16] Kiemeney L. Frequency of familial melanoma and MLM2 gene. Lancet 1995; 345:581.
[17] Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA, . Geographical variation in the penetrance of CDKN2A mutations for melanoma. Journal of the National Cancer Institute 2002; 94(12):894-903.
[18] Begg CB, Orlow I, Hummer AJ, Armstrong BK, Kricker A, Marrett LD, Millikan RC, Gruber SB, Anton-Culver H, Zanetti R, Gallagher RP, Dwyer T, Rebbeck TR, Mitra N, Busam K, From L, Berwick M, . Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. Journal of the National Cancer Institute 2005; 97(20):1507-15.
[19] Bishop JN, Harland M, Randerson-Moor J, Bishop DT. Management of familial melanoma. The lancet oncology 2007; 8(1):46-54.
[20] Niendorf KB, Goggins W, Yang G, Tsai KY, Shennan M, Bell DW, Sober AJ, Hogg D, Tsao H. MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability. Journal of medical genetics 2006; 43(6):501-6.
[21] Goldstein AM, Chan M, Harland M, Hayward NK, Demenais F, Bishop DT, Azizi E, Bergman W, Bianchi-Scarra G, Bruno W, Calista D, Albright LA, Chaudru V, Chompret A, Cuellar F, Elder DE, Ghiorzo P, Gillanders EM, Gruis NA, Hansson J, Hogg D, Holland EA, Kanetsky PA, Kefford RF, Landi MT, Lang J, Leachman SA, MacKie RM, Magnusson V, Mann GJ, Bishop JN, Palmer JM, Puig S, Puig-Butille JA, Stark M, Tsao H, Tucker MA, Whitaker L, Yakobson E, , . Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. Journal of medical genetics 2007; 44(2):99-106.
[22] Magnusson S, Borg A, Kristoffersson U, Nilbert M, Wiebe T, Olsson H. Higher occurrence of childhood cancer in families with germline mutations in BRCA2, MMR and CDKN2A genes. Familial cancer 2008;epub.
[23] Vinarsky V, Fine RL, Assaad A, Qian Y, Chabot JA, Su GH, Frucht H. Head and neck squamous cell carcinoma in FAMMM syndrome. Head Neck. 2009 Apr 9. [Epub ahead of print]
[24] Nagore E, Montoro A, García-Casado Z, Botella-Estrada R, Insa A, Lluch A, López-Guerrero JA, Guillén C. Germline mutations in CDKN2A are infrequent in female patients with melanoma and breast cancer.M elanoma Res. 2009 Jun 30. [Epub ahead of print]
[25] Monnerat C, Chompret A, Kannengiesser C, Avril MF, Janin N, Spatz A, Guinebretière JM, Marian C, Barrois M, Boitier F, Lenoir GM, Bressac-de Paillerets B. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6(4):453-61
[26] Vanneste R, Smith E, Graham G. Multiple Neurofibromas as the Presenting Feature of Familial Atypical Multiple Malignant Melanoma (FAMMM) Syndrome. Am J Med Genet A. 2013 [Epub ahead of print]