Genetic polymorphisms associated with DNA repair genes have been associated with mildly increased melanoma risk in the general population.
(Refer to the Xeroderma pigmentosum section in the Squamous Cell Carcinoma section of this summary for more information.)
Melanoma and pancreatic cancer
A subset of CDKN2A mutation carrier families also displays an increased risk of pancreatic cancer.[88,89] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%. The relative risk has been reported as high as 47.8. Although at least 18 different mutations in p16 have been identified in such families, specific mutations appear to have a particularly elevated risk of pancreatic cancer.[61,92] Mutations affecting splice sites or Ankyrin repeats were found more commonly in families with both pancreatic cancer and melanoma than in those with melanoma alone. The p16 Leiden mutation is a 19-basepair deletion in CDKN2A exon 2 and is a founder mutation originating in the Netherlands. In one major Dutch study, 19 families with 86 members who had melanoma also had 19 members with pancreatic cancer in their families, a cumulative risk of 17% by age 75 years. In this study, the median age of pancreatic cancer onset was 58 years, similar to the median age at onset for sporadic pancreatic cancer. However, other reports indicate that the average age at diagnosis is 5.8 years earlier for these mutation carriers than for those with sporadic pancreatic cancer. Geographic variation may play a role in determining pancreatic risk in these mutation carrier families. In a multicontinent study of the features of germline CDKN2A mutations, Australian families carrying these mutations did not have an increased risk of pancreatic cancer. It was also reported that similar CDKN2A mutations were involved in families with and without pancreatic cancer; therefore, there must be additional factors involved in the development of melanoma and pancreatic cancer. Families with CDKN2A mutations do not appear to have a pattern of site-specific pancreatic cancer only; all of the families identified to date also have some evidence of increased melanoma incidence. Conversely, melanoma-prone families that do not have a CDKN2A mutation have not been shown to have an increased risk of pancreatic cancer.
In a review of 110 families with multiple cases of pancreatic cancer, 18 showed an association between pancreatic cancer and melanoma. Only 5 of the 18 families with cases of both pancreatic cancer and melanoma had individuals with multiple dysplastic nevi. These 18 families were assessed for mutations in CDKN2A; mutations were identified in only 2 of the 18 families, neither of which had a dysplastic nevi phenotype.
The Melanoma-Astrocytoma Syndrome is another phenotype caused by mutations in CDKN2A. The possible existence of this disorder was first described in 1993. A study of 904 individuals with melanoma and their families found 15 families with 17 members who had both melanoma and multiple types of tumors of the nervous system. Another study found a family with multiple melanoma and neural cell tumors that appeared to be caused by loss of p14ARF function or to disruption of expression of p16.