Evidence for a major gene influencing risk of pancreatic cancer

Abstract

Family history of pancreatic cancer, the fifth leading cause of cancer death in the United States, confers a 1.5-13-fold higher risk of developing pancreatic cancer. Pancreatic cancer is associated with several genetic syndromes, including hereditary breast cancer (BRCA2), familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer (HNPCC). However, these syndromes explain little of the observed familial aggregation of pancreatic cancer. We performed complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994 and December 31, 1999. We tested for the presence of a major gene controlling either the "age-at-onset of pancreatic cancer" of "susceptibility to pancreatic cancer," and incorporated smoking data on kindred members as a covariate. We found evidence for involvement of a major gene in the etiology of pancreatic cancer. Whether inheritance was modeled as "age-at-onset" or "susceptibility," nongenetic transmission models were strongly rejected. However, modeling "age-at-onset" provided a better fit to the observed data than did modeling "susceptibility." The most parsimonious models included autosomal-dominant inheritance of a rare allele. Under the age-at-onset model, approximately 0.7% of the population appears to be at high risk of developing pancreatic cancer due to this putative gene, whereas 0.4% of the population is at high risk under the susceptibility model. Inclusion of smoking as a covariate did not significantly improve the fit of these models. This hospital-based segregation analysis of pancreatic cancer found evidence supporting the role of a rare major gene influencing risk of pancreatic cancer. © 2002 Wiley-Liss, Inc.