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. 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. 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. 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. 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.[91,92] The overall lifetime risk of pancreatic cancer in these families ranges from 11% to 17%. The RR 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.[62,95] 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. 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. Some families with CDKN2A mutations may have a pattern of site-specific pancreatic cancer only.[100,101] Conversely, melanoma-prone families that do not have a CDKN2A mutation have not been shown to have an increased risk of pancreatic cancer.