Abstract 1410: Pedigree analysis equally identifies cases of pancreatic cancer in families with BRCA1 and BRCA2 mutations
Authors: Schrock Evelin , Hackmann Karl , Kuhlee Franziska , Jahn Arne , Wagner Johannes , Kahlert Anne-Karin , Porrmann Joseph , Tzschach Andreas , Aust Daniela , Baretton Gustavo , Kast Karin , Wimberger Pauline , Laniado Michael , Kahlert Christoph , Welsch Thilo , Weitz Jürgen , Klink Barbara , Rump Andreas , Gieldon Laura 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in western countries, although lifetime risk is estimated at only 1.3% in the general population. BRCA2 mutations, however, have been attributed with a lifetime risk for PDAC development of 5-10%, while the risk for PDAC development in BRCA1 mutation carriers has been the subject of an ongoing scientific discussion, with current estimates of an increased PDAC risk of only 2-4-fold.
We retrospectively analyzed 180 pedigrees for occurrence of PDAC. All families were counselled for hereditary breast and ovarian cancer (HBOC) within three years (2015 to 2017) at the Center for Hereditary Breast and Ovarian Cancer in Dresden. The pedigrees of 111 families with a pathogenic
BRCA1 germline mutation and of 69 families with a pathogenic BRCA2 germline mutation were available for analysis. Whenever possible genetic testing (NGS or targeted sequencing) was performed using blood and/or tumor tissue of affected individuals. 14 “BRCA1 families” were identified to have at least one family member affected by PDAC (12.6% of families). Three of the patients were available for testing and carrier status could be confirmed in all of them. According to formal genetic risk calculation 6 of the PDAC patients had a mutation carrier risk of 50%, 5 of 25% and 1 of 12.5%. Age of onset (AO) of the disease was known in 13 of the families and the mean AO, calculated for these patients, was 58.7 years. Interestingly, two female Mutation carriers had both breast- and pancreatic cancer and one family with a BRCA1 mutation presented
with two sisters with PDAC. Tumor tissue was available from one of them and sequencing indicated loss-of-heterozygosity, supporting the assumption that the BRCA1 mutation might have been causative for tumorigenesis.
Of the “BRCA2 families” 10 (14,5%) were identified to have one family member each with PDAC. To date, however, none of them was available for genetic testing. 3 of the patients had a mutation carrier risk calculated at 50%, 5 at 25%, 1 at 12.5% and 1 at 6.25%. The mean AO was calculated to be 60.1 years. One female PDAC patient additionally had breast cancer and one of the male patients also suffered from prostate cancer. While the number of families represented in this retrospective study is limited, our observations indicate that BRCA1 mutations might be underdiagnosed in PDAC, especially in patients with an earlier AO. Extensive genetic analyses of PDAC patients will be necessary in order to elucidate this presumption and could also indicate whether additional genetic risk modifiers play a role in PAC development in BRCA1/2 families.
Citation Format: Evelin Schrock, Karl Hackmann, Franziska Kuhlee, Arne Jahn, Johannes Wagner, Anne-Karin Kahlert, Joseph Porrmann, Andreas Tzschach, Daniela Aust, Gustavo Baretton, Karin Kast, Pauline Wimberger, Michael Laniado, Christoph Kahlert, Thilo Welsch, Jürgen Weitz, Barbara Klink, Andreas Rump, Laura Gieldon. Pedigree analysis equally identifies cases of pancreatic cancer in families with BRCA1 and BRCA2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1410.