Ozcelik et al. (1997) investigated the contribution of germline BRCA2 mutations to the development of pancreatic cancer in 41 patients seen over a 4-month period, and selected without regard for family history. Mutations were identified in 2 patients ... Ozcelik et al. (1997) investigated the contribution of germline BRCA2 mutations to the development of pancreatic cancer in 41 patients seen over a 4-month period, and selected without regard for family history. Mutations were identified in 2 patients (4.9%); one had a previously undescribed 6076delGTTA mutation, and the other had a 6174delT mutation (600185.0009). The latter patient was 1 of 13 Jewish individuals in the cohort. In a subsequent study of 26 pancreatic cancers in Jewish individuals seen over a 15-year period, they found the 6174delT mutation in 3; no 6174delT mutations were identified in 55 non-Jewish pancreatic controls. The investigators suggested that the ability to identify a population at high risk for the development of pancreatic cancer might provide an opportunity to develop and evaluate prevention and early detection protocols aimed at reducing mortality. To investigate the role of germline mutations in the etiology of pancreatic cancer, Murphy et al. (2002) analyzed samples from patients from kindreds in which 3 or more family members were affected with the disease, at least 2 of which were first-degree relatives. By direct sequencing of constitutional DNA, they analyzed 4 tumor suppressor candidate genes: MAP2K4 (601335), MADH4 (600993), ACVR1B (601300), and BRCA2. These genes are mutated in clinically sporadic pancreatic cancer, but germline mutations had either not been reported or were anecdotal in familial pancreatic cancer. In the first 3 of the 4 genes, no germline mutations were found, suggesting that they are unlikely to account for a significant number of inherited pancreatic cancers. On the other hand, BRCA2 gene sequencing revealed that 5 patients from the 29 kindreds tested (17.2%) had mutations that had previously been reported to be deleterious; a point mutation (met192 to thr) of unknown significance was also identified. Three patients harbored the common 6174delT frameshift mutation (600185.0009), 1 had the splice site mutation IVS16-2A-G, and 1 had a novel splice site mutation IVS15-1G-A. A family history of breast cancer was reported in 2 of the 5 BRCA2 mutation carriers; none reported a family history of ovarian cancer. These findings confirmed an increased risk of pancreatic cancer in individuals with BRCA2 mutations and identified germline BRCA2 mutations as the most common inherited genetic alteration in familial pancreatic cancer.
Genetic studies of familial pancreatic cancer have led to the identification of mutations in the BRCA2 gene in approximately 12 to 20% of families, often in the absence of cases of breast or ovarian carcinoma (McWilliams et al., ... Genetic studies of familial pancreatic cancer have led to the identification of mutations in the BRCA2 gene in approximately 12 to 20% of families, often in the absence of cases of breast or ovarian carcinoma (McWilliams et al., 2005).