Inherited predisposition to pancreatic adenocarcinoma: Role of family history and germ-line p16, BRCA1, and BRCA2 mutations

Susceptibility to pancreatic adenocarcinoma appears to be linked to germ-li ne mutations in genes causing various familial cancer syndromes. The object ives of this study were to estimate the proportion of unselected pancreatic cancer patients belonging to hereditary cancer syndrome families and to de termine the frequency of p16, BRCA1, BRCA2, hMSH2, and hMLH1 germ-line muta tions in patients with a personal or family history of cancer. The study po pulation consisted of 102 patients with histologically verified pancreatic adenocarcinoma, unselected for age, sex, family history, or ethnic origin. Patients completed a family history questionnaire and provided blood for mu tation analysis. Three-generation pedigrees were constructed and classified as high risk/familial, intermediate risk/familial, intermediate risk/nonfa milial, or low risk according to defined criteria. High- and intermediate-r isk cases were analyzed for germ-line mutations using a combination of meth ods. Thirty-eight of 102 (37%) patients were characterized as high or inter mediate risk, and the remainder were classified as low risk. Germ-line muta tions were identified in five (13%) of these cases [one in p16 (I49S); one in BRCA1 (5382 insC); and three in BRCA2 (6174delT)]. The BRCA1 and BRCA2 m utations were identified in Ashkenazi Jewish patients. Four of the mutation carriers had strong family histories of the syndromes associated with the mutated genes, No mutations were identified in patients in whom the sole ri sk factor was a family history of pancreatic cancer, and only one mutation was found among patients with early-onset disease. We conclude that known c auses of genetic predisposition are an important risk factor in a small pro portion of pancreatic cancer patients, especially if associated with a stro ng family history of syndromes associated with the disease. The lack of det ectable germ-line mutations in most high- and intermediate-risk cases sugge sts that there are probably additional, as yet unidentified genes predispos ing to this disease.