Abstract 09: Contribution of known and novel BRCA-mediated DNA repair pathway genes to pancreatic cancer susceptibility

Abstract

Abstract Although 10% of pancreatic adenocarcinoma (PC) cases cluster in families, the genetic basis underlying most familial PC cases is unknown. Mutations in the BRCA-pathway genes (BRCA1/2, PALB2) are rare causes of PC, but may have a more significant role in French-Canadians (FC), a population enriched with founder mutations in these genes. We have hypothesized that 1) mutations in the BRCA-pathway genes represent 5% of the genetic susceptibility to PC in French-Canadians and, 2) that familial PC cases without mutations in known PC susceptibility genes have causative mutations in other tumor suppressor genes. In a prospective clinic-based study, we screened unselected incident PC cases with FC ancestry (n=52) for the common FC founder mutations (n=20) and uncovered the PALB2:c.2323C>T and BRCA2:c.3170_3174delAGAAA founder mutations in 2 kindreds. Additionally, we identified a novel loss-of-function BRCA2 mutation in a 3rd FC family. Since the role of PALB2 as a PC susceptibility gene is not well established, we provide supporting evidence by confirming mutation segregation with disease, as well as loss of the wild-type allele in the corresponding tumours. Of note, both BRCA2 mutation carriers were treated with platinum-based chemotherapy, targeting DNA repair defects in their tumors, and demonstrated marked tumor responses. To search for novel genetic causes of PC, we identified 99 high-risk families, including cases with 2 or more PC-affected relatives or early onset PC presentations, collected prospectively through the Quebec and Ontario Pancreas Cancer Studies. We employed exome sequencing to interrogate all of the protein-coding regions of the human genome in these 99 high-risk cases, as well as in 13 PC-affected relatives. Although these investigations did not reveal a single gene to explain the unaccounted fraction of familial PC, we identified 9 putative familial PC genes with rare, loss-of-function variants among multiple high-risk families. Two of these candidate familial PC genes are involved in the BRCA-mediated DNA repair pathway. Our data suggest that BRCA-pathway mutations may contribute significantly to PC susceptibility in French-Canadians and that mutation carriers have improved clinical outcomes if treated with agents that target BRCA-deficient cells. As well, we have identified 9 novel familial PC candidate genes, including 2 genes that are involved in the BRCA-pathway. Citation Format: Alyssa Smith, Robert Grant, Anita Hall, Najmeh Alirezaie, Spring Holter, Thomas Whelan, Iris Selander, Treasa McPherson, John McPherson, Atilla Omeroglu, Jacek Majewski, William Foulkes, Steven Gallinger, George Zogopoulos. Contribution of known and novel BRCA-mediated DNA repair pathway genes to pancreatic cancer susceptibility. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 09. doi:10.1158/1538-7445.CANSUSC14-09