Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas.

Germline mutations in BRCA2 predispose carriers to the development of breast, ovarian, and a variety of other cancers. The original localization of the BRCA2 gene was aided by its homozygous deletion in a pancreatic carcinoma; indeed, an excess of pancreatic carcinoma has been seen in some BRCA2 cancer families. To determine the involvement of BRCA2 in pancreatic carcinomas, we screened for BRCA2 alterations in an unselected panel of 41 adenocarcinomas of the pancreas (30 pancreatic adenocarcinoma xenografts and 11 pancreatic cancer cell lines). Of the 15 (27%) that had allelic loss at the BRCA2 locus, 4 (9.8%) had abnormalities in the second allele upon screening of the entire BRCA2 gene by in vitro synthesized protein assay. Three of the four mutations were considered germline in origin (7.3% overall; two were confirmed in normal tissue, and one was the 6174delT mutation from the pancreatic cancer cell line CAPAN-1, for which normal tissue was unavailable). The identification of two 6174delT mutations in this series prompted us to evaluate the prevalence of this mutation in an overlapping consecutive series of 245 patients who underwent pancreatoduodenectomy for adenocarcinoma of the pancreas. Sequence analysis of this limited region of the gene identified two additional mutations: (a) one additional germline 6174delT mutation (2 of 245, 0.8% overall); and (b) a second nearby germline 6158insT mutation. One of the patients with a germline mutation had a single relative with breast cancer, and another had a single relative with prostate cancer. None had a family history of pancreatic cancer. The incidence of germline BRCA2 mutations in apparently sporadic pancreatic cancer may be at least as high as in breast or ovarian cancer. Our results suggest that some familial risks for carcinoma will be evident only through a population-based application of gene screening techniques because a low disease penetrance of the germline mutations in some families often evades clinical suspicion.