1. ¹Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205-2196, USA
2. ²Departments of Laboratory Medicine and Pathology, and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
3. ³Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21205-2196, USA
4. ⁴Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD 21205-2196, USA
5. ⁵Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD 21205-2196, USA

Correspondence: M Goggins, Departments of Pathology, Medicine, and Oncology, the Johns Hopkins Medical Institutions, 632 Ross Bldg., 720 Rutland Ave., Baltimore, MD 21205-2196, USA. E-mail: mgoggins@jhmi.edu

Received 2 August 2004; Revised 11 November 2004; Accepted 16 November 2004; Published online 4 April 2005.

Abstract

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.