Opinion statement
Families that have several relatives with melanoma, multiple primary melanomas in one individual, younger than average ages of melanoma onset, and/or the presence of both pancreatic cancer and melanoma may be suggestive of a hereditary melanoma syndrome and are candidates for genetic counseling and risk assessment. Genetic counseling for hereditary melanoma presents many complexities. Only a minority of hereditary melanoma cases have been attributed to a single genetic factor, CDKN2A. Both the frequency and the penetrance of CDKN2A mutations has been shown to be dependent on multiple factors. The clinical utility of genetic testing for hereditary melanoma families is debatable because CDKN2A status may not impact medical management in patients with melanoma. No standard medical management guidelines exist for families with CDKN2A mutations; however, family history of melanoma and pancreatic cancer may warrant further discussion. Clinicians should discuss the clinical and psychological implications before genetic testing. Genetic counseling and pretest education regarding melanoma risk factors provides an opportunity to increase knowledge and understanding of melanoma risk, while addressing psychological risks and concerns.
Similar content being viewed by others
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Goldstein A, Chan M, Harland M, Hayward N, Demenais F, Bishop DT, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44:99–106.
Bishop DT, Demenais F, Goldstein A, Bergman W, Bishop J, Bressac-de Paillerets B, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94:894–903.
Leachman S, Carucci J, Kohlmann L, Banks K, Asgari M, Bergman W, et al. Selection criteria for genetic assessment of patients with familial melanoma. J Am Acad Dermatol. 2009;61:677.e1–14.
Njauw CNJ, Kim I, Piris A, Gabree M, Taylor M, Lane AM, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One. 2012;7:e35295.
Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105:1607–16.
Monnerat C, Chompret A, Kannengiesser C, Avril M, Janin N, Spatz A, et al. BRCA1, BRCA2, TP53, and CDKN2A germline mutations in patients with breast cancer and cutaneous melanoma. Fam Cancer. 2007;6:453–61.
Cruz C, Teule A, Caminal J, Blanco I, Piulats J. Uveal melanoma and BRCA1/BRCA2 genes: a relationship that needs further investigation. J Clin Oncol. 2011;29:e827–9.
Curiel-Lewandrowski C, Curiel-Lewandrowski C, Speetzen L, Cranmer L, Warneke J, Loescher L. Multiple primary cutaneous melanomas in Li-Fraumeni syndrome. Arch Dermatol. 2011;147:248–50.
Goldstein A, Chan M, Harland M, Gillanders E, Hayward N, Avril M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818–28.
Bertolotto C, Lesuer F, Giuliano S, Strub T, de Lichy M, Bille K, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480:94–8.
Bradford P, Goldstein A, Tamura D, Khan S, Ueda T, Boyle J, et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 2011;48:168–76.
SEER fact sheets: melanoma of the skin. National Cancer Institute Surveillance, Epidemiology, and End Results Program. From: http://seer.cancer.gov/statfacts/html/melan.html. Accessed 20 Dec 2013.
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635–48.
Austin MT, Xing Y, Hayes-Jordan AA, Lally KP, Cormier JN. Melanoma incidence rises for children and adolescents: an epidemiologic review of pediatric melanoma in the United States. J Pediatr Surg. 2013;48(11):2207–13.
Erdmann F, Lortet-Tieulen J, Schuz J, Zeeb H, Greinert R, Breitbar EW, et al. International trends in the incidence of malignant melanoma 1953-2008—are recent generations at higher or lower risk? Int J Cancer. 2013;132(2):385–400.
Gandini S, Sera F, Cattaruzz MS, Pasquini P, Abeni D, Boyle P, et al. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer. 2005;41(1):28–44.
Gandini S, Sera F, Cattaruzza MS, Pasquini P, Picconi O, Boyle P, et al. Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure. Eur J Cancer. 2005;41(1):45–60.
Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, et al. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005;41(14):2040–59.
Goldstein A, Tucker M. Dysplastic nevi and melanoma. Cancer Epidemiol Biomarkers Prev. 2013;22:528–32.
Crombie IK. Variation of melanoma incidence with latitude in North America and Europe. Br J Cancer. 1979;40:774–81.
Whiteman DC, Watt P, Purdie DM, Hughes MC, Hayward NK, Green AC. Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. J Natl Cancer Inst. 2003;95:806–12.
van der Ree J, Krijnen P, Gruis N, de Snoo F, Vasen H, Putter H, et al. Clinical and histologic characteristics of malignant melanoma in families with a germline mutation in CDKN2A. J Am Acad Dermatol. 2011;65:281–8. This study of CDKN2A phenotypes examined individuals in the Netherlands with a founder CDKN2A mutation (p16-Leiden). Consistent with other studies of CDKN2A mutation carriers, this study found younger age of onset and a greater number of individuals with multiple primary melanomas in individuals with CDKN2A mutations versus controls. They also report histological differences, including more superficial spreading and less nodular and lentiginous melanomas, in CDKN2A mutation carriers versus the control group. They conclude that their findings support that melanomas in individuals with CDKN2A mutations develop through a different pathway than later-onset, sporadic melanomas.
Goldstein AM. Familial melanoma, pancreatic cancer and germline CDKN2A mutations. Hum Mutat. 2004;23(6):630.
McKenzie HA, Fung C, Becker TM, Irvine M, Mann GJ, Kefford RF, et al. Predicting functional significance of cancer-associated p16(INK4a) mutations in CDKN2A. Hum Mutat. 2010;31(6):692–701.
Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013;19(19):5320–8.
Puntervoll H, Yang X, Vetti H, Bachmann I, Avril M, Benfodda M, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013;50:264–70. This study describes characteristics of individuals with inherited mutations in CDK4. The authors note that germline CDK4 mutations are rare. They conclude that the phenotype of individuals with inherited CDK4 mutations, which includes younger than average age of melanoma onset, multiple primary melanomas, multiple relatives with melanoma, and relatives with pancreatic cancer, is similar to the phenotype of individuals with CDKN2A germline mutations.
Cust A, Goumas C, Vuong K, Davies J, Barrett J, Holland E, et al. MC1R genotype as a predictor of early-onset melanoma, compared with self-reported and physician-measured traditional risk factors: an Australian case-control-family study. BMC Cancer. 2013;4:406.
Mitra D, Luo X, Morgan A, Wang J, Hoang M, Lo J, et al. An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background. Nature. 2012;491:449–53.
Begg C, Orlow I, Hummer A, Armstrong B, Kricker A, Marrett L, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. 2005;97:1507–15.
Maubec E, Chaudru V, Mohamdi H, Blondel C, Margaritte-Jeannin P, Forget S, et al. 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. 2012;67:1257–64. This study examines the correlation between the number of relatives affected with melanoma and CDKN2A mutation status in a French cohort. In the context of the study, the authors also review the features associated with CDKN2A mutation status. The results of this study reveal that a greater number of relatives with melanoma correlate to a higher probability of having a germline CDKN2A mutation.
Tsao H, Zhang X, Kwitkiwski L, Finkelstein D, Sober A, Haluska F. Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma. Arch Dermatol. 2000;136:1118–22.
Pedace L, De Simone P, Castori M, Sperduti I, Silipo V, Eibenschutz L, et al. Clinical features predicting identification of CDKN2A mutations in Italian patients with familial cutaneous melanoma. Cancer Epidemiol. 2011;35:e116–20.
Blackwood MA, Holmes R, Synnestvedt M, Young M, George C, Yang H, et al. Multiple primary melanoma revisited. Cancer. 2002;94:2248–55.
Monzon J, Liu L, Brill H, Goldstein A, Tucker M, From L, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med. 1998;338:879–87.
Nikolaou V, Kang X, Stratigos A, Gogas H, Latorre MC, Gabree M, et al. Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma. Br J Dermatol. 2011;165:1219–22.
Whiteman D, Milligan A, Welch J, Green A, Hayward N. Germline CDKN2A mutations in childhood melanoma. JNCI. 1997;89(19):1460.
Berg P, Wennberg A-M, Tuominen R, Sander B, Rozell B, Platz A, et al. Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma. Melanoma Res. 2004;14(4):251–5.
de Snoo F, Bishop DT, Bergman B, van Leeuwen I, van der Drift C, van Nieuwpoort F, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res. 2008;14:7151–7.
Harinck F, Kluijt I, van der Stoep N, Oldenburg R, Wagner A, Aalfs C, et al. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas. J Med Genet. 2012;49:362–5.
Ghiorzo P, Fornarini G, Sciallero S, Battistuzzi L, Belli F, Bernard L, et al. CDKN2A is the main susceptibility gene in Italian pancreatic cancer families. J Med Genet. 2012;49:164–70.
McWilliams R, Wieben E, Rabe K, Pedersen K, Wu Y, Sicotte H, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur J Hum Genet. 2010;19:472–8.
Tucker M, Fraser M, Goldstein A, Struewing J, King M, Crawford J, et al. A natural history of melanomas and dysplastic nevi. Cancer. 2002;94:3192–209.
Goldstein A, Martinez M, Tucker M, Demenais F. Gene-covariate interaction between dysplastic nevi and the CDKN2A gene in American melanoma-prone families. Cancer Epidemiol Biomarkers Prev. 2000;9:889–94.
Hussussian C, Struewing J, Goldstein A, Higgins P, Ally D, Sheahan M, et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8(1):15–21.
American Society of Clinical Oncology policy statement update. Genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):2397–406.
Robson M, Storm C, Weitzel J, Wollins D, Offit K. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28:893–901.
Kefford R, Newton Bishop J, Bergman W, Tucker M. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the melanoma consortium. J Clin Oncol. 1999;17(10):3245–51.
Demenais F, Mohamdi H, Chaudru V, Goldstein A, Bishop J, Bishop D, et al. Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst. 2010;102:1568–83.
Gerstenblith M, Goldstein A, Tucker M, Fraser M. Genetic testing for melanoma predisposition: current challenges. Cancer Nurs. 2007;30(6):454–61.
Hansen C, Wadge L, Lowstuter K, Boucher K, Leachman S. Clinical germline genetic testing for melanoma. Lancet. 2004;5:314–9.
de Snoo F, Bergman W, Gruis N. Familial melanoma: a complex disorder leading to controversy on DNA testing. Familial Cancer. 2003;2:109–16.
Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet S, et al. Genetic cancer risk assessment and counseling: recommendation of the National Society of Genetic Counselors. J Genet Couns. 2004;13(2):83–114.
Gomy I, Diz M. Hereditary cancer risk assessment: essential tools for a better approach. Hered Cancer Clin Pract. 2013;11(16):1–8.
Weitzel J, Blazer K, MacDonald D, Culver J, Offit K. Genetics, genomics, and cancer risk assessment. CA Cancer J Clin. 2011;61:327–59.
Caini S, Gandini S, Sera F, Raimondi S, Fargnoli M, Boniol M, et al. Meta-analysis of risk factors for cutaneous melanoma according to anatomical site and clinico-pathological variant. Eur J Cancer. 2009;45:3054–63.
Wang W, Niendorf K, Patel D, Blackford A, Marroni F, Sober A, et al. Estimating CDKN2A carrier probability and personalizing cancer risk assessments in hereditary melanoma using MelaPro. Cancer Res. 2010;70(2):552–9.
Tsao H, Niendorf K. Genetic testing in hereditary melanoma. J Am Acad Dermatol. 2004;51(5):803–8.
Canto M, Harinck F, Hruban R, Offerhaus G, Poley J, Kamel I, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013;62:339–47.
National Comprehensive Cancer Network. Melanoma, version 2.2014. From: http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed 20 Dec 2013.
Champine M, Kohlmann W, Leachman S. Genetic counseling and testing for hereditary melanoma: an updated guide for dermatologists. Genetics. 2013;S2:004. This article provides a summary of factors associated with melanoma risk assessment including environmental exposure, phenotype, and genetic status. They also discuss the process of genetic counseling and testing for CDKN2A.
Center for Disease Control. Skin cancer: prevention. From http://www.cdc.gov/cancer/skin/basic_info/prevention.htm. Accessed 20 Dec 2013.
Domchek S, Bradbury A, Garber J, Offit K, Robson M. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31:1267–70.
Aspinwall L, Taber J, Leaf S, Kohlmann W, Leachman S. Melanoma genetic counseling and test reporting improve screening adherence among unaffected carriers 2 years later. Cancer Epidemiol Biomarkers Prev. 2013;22:1687–97. This study assesses the long term effect of CDNK2A genetic counseling and testing on the adherence to clinical and self skin examinations. The results of this study show increased adherence to clinical and self skin examinations in unaffected CDKN2A mutation carriers. The authors conclude that these findings suggest a benefit to genetic counseling and testing for CDKN2A in unaffected relatives of CDKN2A mutation carriers.
de Snoo F, Riedijk S, van Mil A, Bergman W, ter Huurne J, Timman R, et al. Genetic testing in familial melanoma: uptake and implications. Psychooncology. 2008;17:790–6.
Glanz K, Volpicelli K, Kanetsky PA, Ming ME, Schuchter LM, Jepson C, et al. Melanoma genetic testing, counseling, and adherence to skin cancer prevention and detection behaviors. Cancer Epidemiol Biomarkers Prev. 2013;22:607–14.
Aspinwall L, Leaf S, Dola R, Kohlmann W, Leachman S. Patterns of photoprotection following CDKN2A/p16 genetic test reporting and counseling. J Am Acad Dermatol. 2009;60:745–57.
Compliance with Ethics Guidelines
Conflict of Interest
Michele Gabree, Devanshi Patel, and Linda Rodgers declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gabree, M., Patel, D. & Rodgers, L. Clinical Applications of Melanoma Genetics. Curr. Treat. Options in Oncol. 15, 336–350 (2014). https://doi.org/10.1007/s11864-014-0282-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11864-014-0282-8