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Genetics of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Melanoma

Table 6. Environmental Exposures Other Than Sunlight Associated with Melanomaa continued...

A comparison of clinical features from 182 patients with CDKN2A mutations and 7,513 individuals without mutations found that individuals with CDKN2A mutations had a statistically significant younger age at diagnosis (mean age at diagnosis: 39.0 years vs. 54.3 years; P < .001). There was also a 5-year cumulative incidence of a second melanoma of 23.4% in mutation carriers and a rate of 2.3% in mutation-negative controls.[86] An Italian study performed genotype-phenotype correlations in 100 families with familial melanoma to determine clinical features predictive of the identification of a CDKN2A mutation. Probands with multiple primary melanomas, at least one melanoma with Breslow thickness greater than 0.4 mm, and more than three affected family members had a greater than 90% likelihood of having a mutation; probands with none of these features had less than a 1% likelihood of having a CDKN2A mutation. The most predictive feature was multiple primary melanomas.[87] Results from the Genes, Environment, and Melanoma study showed that first-degree relatives of CDKN2A mutation carriers with melanoma had an approximately 50% increased risk of cancers other than melanoma, compared with first-degree relatives of other melanoma patients.[88] Cancers with increased risk in this population included gastrointestinal cancers (relative risk [RR], 2.4; 95% CI, 1.4–3.7), pancreatic cancers (RR, 7.4; 95% CI, 2.3–18.7), and Wilms tumor (RR, 40.4; 95% CI, 3.4–352.7).

CDKN2A exon 1ß mutations (p14ARF) have been identified in a small percentage of families negative for p16INK4a mutations. In a study of 94 Italian families with two or more cases of melanoma, 3.2% of families had mutations in p14ARF.[89] At this time, testing for p14ARF is not commercially available.

Melanoma and pancreatic cancer

A subset of CDKN2A mutation carrier families also displays an increased risk of pancreatic cancer.[90,91] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%.[92] The RR has been reported as high as 47.8.[93] 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.[62,94] 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-base pair 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.[95] 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.[96] 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.[97] It was also reported that similar CDKN2A mutations were involved in families with and without pancreatic cancer;[98] 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.[99] Conversely, melanoma-prone families that do not have a CDKN2A mutation have not been shown to have an increased risk of pancreatic cancer.[95]

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