Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations

Germline mutations of the CDKN2A tumor suppressor gene have been identified in melanoma kindreds linked to 9p21, and pancreatic adenocarcinoma is the second most common malignancy in some of these families. We hypothesized th at unselected patients with both primary cancers, i.e., pancreatic cancer a nd malignant melanoma, have a genetic predisposition to tumor development, and that this susceptibility may be due to germline CDKN2A mutations. Fourt een patients, with both pathologically verified pancreatic adenocarcinoma a nd melanoma, were assessed for germline CDKN2A mutations by polymerase chai n reaction amplification and sequencing of six overlapping fragments encomp assing exons 1 alpha and 2. A yeast two-hybrid assay was used to assess the functional consequences of CDKN2A variants. Germline CDKN2A mutations were identified in 2/14 patients: 149S, a novel substitution in exon 1 alpha, a nd M531, a previously reported missense mutation in exon 2. Both variants l ead to compromised CDKN2A function. We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer. and that this predisposition is, in some cases, d ue to germline CDKN2A mutations. This finding has important implications no t only For the proband, but also for other family members. (C) 2000 Wiley-L iss, Inc.