INCREASED RISK OF PANCREATIC-CANCER IN MELANOMA-PRONE KINDREDS WITH P16(INK4) MUTATIONS

Background. A gene on chromosome 9p, p16(INK4), has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the functio n of the p16(INK4) protein (p16M alleles) cosegregated with the diseas e. By contrast, in the other nine kindreds the mutation did not alter the function of p16(INK4) (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of fa milies. Methods. We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in t he kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of can cer cases observed with the number expected. Results. The risk of inva sive melanoma was increased by a factor of 75 in kindreds with p16W al leles and a factor of 38 in kindreds with p16W alleles. Although this difference was not significant (P=0.14), there was a striking differen ce in the risk of other tumors. In kindreds with p16M alleles, the ris k of pancreatic cancer was increased by a factor of 13 in the prospect ive period (2 cases observed, 0.15 expected; standardized incidence ra tio, 13.1; 95 percent confidence interval, 1.5 to 47.4) and by a facto r of 22 in the entire period (7 cases observed, 0.32 expected; standar dized incidence ratio, 21.8; 95 percent confidence interval, 8.7 to 44 .8). In contrast, we found no cases of pancreatic cancer in kindreds w ith p16W alleles. Conclusions. The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic facto rs, such as the kind of mutation found in p16(INK4), may explain the i nconsistent occurrence of other cancers in these kindreds.