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 localiza tion of the BRCA2 gene was aided by its homozygous deletion in a pancr eatic carcinoma; indeed, an excess of pancreatic carcinoma has been se en in some BRCA2 cancer families. To determine the involvement of BRCA 2 in pancreatic carcinomas, we screened for BRCA2 alterations in an un selected panel of 41 adenocarcinomas of the pancreas (30 pancreatic ad enocarcinoma xenografts and II pancreatic cancer cell lines). Of the 1 5 (27%) that had allelic loss at the BRCA2 locus, 4 (9.8%) had abnorma lities 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 no rmal tissue, and one was the 6174delT mutation from the pancreatic can cer cell line CAPAN-1, for which normal tissue was unavailable). The i dentification 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 adenoc arcinoma of the pancreas. Sequence analysis of this limited region of the gene identified two additional mutations: (a) one additional germl ine 6174delT mutation (2 of 245, 0.8% overall); and (b) a second nearb y germline 6158insT mutation. One of the patients with a germline muta tion had a single relative with breast cancer, and another had a singl e relative with prostate cancer. None had a family history of pancreat ic cancer. The incidence of germline BRCA2 mutations in apparently spo radic pancreatic cancer may be at least as high as in breast or ovaria n canter. Our results suggest that some familial risks for carcinoma w ill be evident only through a population-based application of gene scr eening techniques because a low disease penetrance of the germline mut ations in some families often evades clinical suspicion.