TY - JOUR
T1 - Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer
AU - Martin, Sean T.
AU - Matsubayashi, Hiroyuki
AU - Rogers, Carmelle D.
AU - Philips, Juliet
AU - Couch, Fergus J.
AU - Brune, Kieran
AU - Yeo, Charles J.
AU - Kern, Scott E.
AU - Hruban, Ralph H.
AU - Goggins, Michael
PY - 2005/5/19
Y1 - 2005/5/19
N2 - Germline BRCA2 mutations predispose to the development of pancreatic cancer. A polymorphic stop codon in the coding region of BRCA2 (K3326X) has been described, and although an initial epidemiological study suggested it was not disease causing, subsequent studies have been inconclusive. To investigate the biological significance of the K3326X polymorphism, we determined its prevalence in patients with sporadic and familial pancreatic cancer. Using a case-control design, we studied 250 patients with resected sporadic pancreatic adenocarcinomas, 144 patients with familial pancreatic adenocarcinoma, 115 spouses of patients with pancreatic cancer, and a disease control group of 135 patients without a personal history of cancer who had undergone cholecystectomy for non-neoplastic disease. The K3326X polymorphism was detected using heteroduplex analysis and DNA sequencing. The BRCA2 K3326X polymorphism was significantly more prevalent in individuals with familial pancreatic cancer: 8/144 (5.6%) vs 3/250 controls (1.2%) (odds ratio, 4.84; 95% CI, 1.27-18.55, P < 0.01). One K3326X carrier with familial pancreatic cancer carried an alteration (IVS 16-2A > G) suspected to be deleterious. Excluding this case did not alter the significance of the association (OR: 4.24, P < 0.01). In contrast, there was no difference in prevalence among individuals with sporadic pancreatic cancer - 7/250 (OR: 2.37, 95% CI: 0.61-9.27). The increased prevalence of the BRCA2 K3326X polymorphism in patients with familial pancreatic cancer suggests that this polymorphism is deleterious and contributes to pancreatic cancer risk.
AB - Germline BRCA2 mutations predispose to the development of pancreatic cancer. A polymorphic stop codon in the coding region of BRCA2 (K3326X) has been described, and although an initial epidemiological study suggested it was not disease causing, subsequent studies have been inconclusive. To investigate the biological significance of the K3326X polymorphism, we determined its prevalence in patients with sporadic and familial pancreatic cancer. Using a case-control design, we studied 250 patients with resected sporadic pancreatic adenocarcinomas, 144 patients with familial pancreatic adenocarcinoma, 115 spouses of patients with pancreatic cancer, and a disease control group of 135 patients without a personal history of cancer who had undergone cholecystectomy for non-neoplastic disease. The K3326X polymorphism was detected using heteroduplex analysis and DNA sequencing. The BRCA2 K3326X polymorphism was significantly more prevalent in individuals with familial pancreatic cancer: 8/144 (5.6%) vs 3/250 controls (1.2%) (odds ratio, 4.84; 95% CI, 1.27-18.55, P < 0.01). One K3326X carrier with familial pancreatic cancer carried an alteration (IVS 16-2A > G) suspected to be deleterious. Excluding this case did not alter the significance of the association (OR: 4.24, P < 0.01). In contrast, there was no difference in prevalence among individuals with sporadic pancreatic cancer - 7/250 (OR: 2.37, 95% CI: 0.61-9.27). The increased prevalence of the BRCA2 K3326X polymorphism in patients with familial pancreatic cancer suggests that this polymorphism is deleterious and contributes to pancreatic cancer risk.
KW - BRCA2
KW - Familial pancreatic cancer
KW - K3326X
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U2 - 10.1038/sj.onc.1208411
DO - 10.1038/sj.onc.1208411
M3 - Article
C2 - 15806175
AN - SCOPUS:19944414645
SN - 0950-9232
VL - 24
SP - 3652
EP - 3656
JO - Oncogene
JF - Oncogene
IS - 22
ER -