Hereditary Melanoma

TON - March/April 2014 Vol 7 No 2

May 5th is Melanoma Monday, as designated by the American Academy of Dermatology.1 Melanoma is a form of cancer that begins in the melanocytes. It may originate in the skin, eye, or intestines. As most people know, exposure to sunlight and artificial sources of ultraviolet radiation, such as tanning beds, are the main risk factors for cutaneous melanoma.2 In addition to sun exposure, other risk factors include pigmentary characteristics, nevi, immunosuppression, family history, and personal history. Similar to all cancers, a proportion of melanoma is due to inherited predisposition. Approximately 10% of cutaneous melanoma cases are attributed to inherited factors.3

There is an inverse correlation between melanoma risk and skin color. Lighter skinned ethnic groups are more likely to develop melanoma than darker skinned ethnic groups. Therefore, clinicians should be more concerned about a possible genetic link when a melanoma is present in an individual of darker skin. Additionally, individuals with multiple nevi and/or atypical nevi are at an increased risk of melanoma, as are individuals who have undergone organ transplants. The associated risk with organ transplants is hypothesized to be due to the effects of immunosuppressive therapy. A family history of melanoma, personal history of melanoma, and/or a personal history of nonmelanoma skin cancer are also risk factors for melanoma.2

Hereditary melanoma is defined as 3 or more diagnoses in a family.3 The main gene associated with inherited cutaneous melanoma is CDKN2A, cyclin-dependent kinase inhibitor 2A. It controls the passage of cells through the cell cycle allowing for repair of DNA damage prior to cellular replication. Mutations in the CDKN2A gene are estimated to account for 20% to 40% of familial melanoma cases.4 This gene encodes 2 proteins: p16 and p14. Thus, it is also often referred to as p16. Further, variants in the MC1R gene have been associated with CDKN2A penetrance. The reported lifetime risk of developing melanoma varies widely across the literature, ranging from 28% to 91% by age 80. Risk also varies based on geographic location. The average age of diagnosis for the first melanoma is 39 years. In addition to being at increased risk for melanoma, individuals with a mutation in CDKN2A are also at increased lifetime risk for pancreatic cancer, ranging from 11% to 17%.5

CDK4, cyclin-dependent kinase 4, is also an important part of the cell cycle and is in the same signaling pathway as CDKN2A. As with CDKN2A, the average age of diagnosis of the first melanoma is 39 years, individuals are prone to multiple melanomas, and they are more likely to have atypical nevi. Mutations in CDK4 are thought to be rare, as few families have been reported in the literature. However, analysis of the CDK4 gene has not been common practice and will likely increase with its incorporation on multigene panels. To date, all of these families have had a mutation that affects the ability of CDK4 to bind with CDKN2A. Hereditary melanoma families negative for mutations in CDKN2A should be evaluated for mutations in the CDK4 gene.6 Genetic counseling and possibly CDKN2A/CDK4 testing should be offered for individuals with 3 or more relatives on the same side of the family with melanoma, 3 or more primary melanomas in one individual, or individuals with pancreatic cancer and melanoma on the same side of the family.3

In addition to being linked to mutations in CDKN2A and CDK4, melanoma may also be part of other cancer predisposition syndromes. Therefore, it is important to take into account all cancers in an individual’s personal and family history when assessing inherited risk. Individuals with xeroderma pigmentosum (XP) have a high risk of developing melanoma, greater than a 2000-fold increase by age 20 with the average first diagnosis occurring around age 22. XP is an autosomal recessive condition characterized by severe ultraviolet light photosensitivity, as well as ocular abnormalities and sometimes neurological manifestations. Individuals have been reported with hundreds of primary skin cancers.7 Werner syndrome is also an autosomal recessive condition. It is characterized by features of premature aging in the second decade of life and is due to mutations in the WRN gene. It is associated with an increased risk for acral lentiginous melanomas and mucosal melanomas.8 Melanoma has also been reported in hereditary breast and ovarian cancer families, specifically those with BRCA2 mutations,9 Cowden syndrome,10 and Li-Fraumeni syndrome.11 Additionally, BAP1 mutations have been associated with both uveal and cutaneous melanoma.12

Take-Home Messages

  • Two genes, CDKN2A and CDK4, are associated with hereditary melanoma families. As phenotypic differences are not known, mutations in both genes should be ruled out in at-risk families.
  • Several other inherited syndromes have been shown to have an increased risk for melanoma. Therefore, when assessing a melanoma survivor for inherited risk, all cancers in his or her personal and family history should be taken into account.

References
1. Melanoma Monday®. American Academy of Dermatology website. www.aad.org/spot-skin-cancer/what-we-do/melanoma-Monday. Accessed March 4, 2014.
2. Melanoma. National Cancer Institute website. www.cancer.gov/cancertopics/types/melanoma. Accessed March 4, 2014.
3. Gabree M, Seidel M. Genetic testing by cancer site: skin. Cancer J. 2012;18(4):372-380.
4. Goldstein AM, Chan M, Harland M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66(20):9818-9828.
5. Genetics of skin cancer (PDQ). National Cancer Institute website. www.cancer.gov/cancertopics/pdq/genetics/s-zkin/HealthProfessional/page4. Accessed March 4, 2014.
6. Puntervoll HE, Yang XR, Vetti HH, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013;50(4):264-270.
7. Bradford PT, Goldstein AM, Tamura D, et al. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair. J Med Genet. 2011;48(3):168-176.
8. Lauper JM, Krause A, Vaughan TL, et al. Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS One. 2013;8(4):e59709.
9. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91(15):1310-1316.
10. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. 2013;50(4):255-263.
11. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1311/. Accessed March 4, 2014.
12. Murali R, Wiesner T, Scoyler RA. Tumours associated with BAP1 mutations. Pathology. 2013;45(2):116-126.

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