Abstract 3397: Whole exome sequencing case-control study implicates truncating variants in ATM as major risk factors in pancreatic cancer
Authors: Scheet Paul , Yu Yao , Chang Kyle , Hildebrandt Michelle , Permuth Jenny , Li Donghui , Huff Chad 
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC), which accounts for 95% of pancreatic cancers, is a leading cause of cancer-related deaths in the world, with a 5-year survival rate of less than 8%. Multiple PDAC susceptibility genes harboring rare pathogenic variants have been identified from familial studies, highlighting the contribution of rare genetic variation to the genetic architecture of the disease. Yet, to date, the majority of variation contributing to the heritable risk of PDAC remains unidentified. To address this gap, we conducted a whole exome sequencing (WES) case-control study on 1591 PDAC cases and 2134 age-matched cancer-free controls of European ancestry. After jointly calling all cases and controls, we applied a burden test to identify genes with an excess of rare coding variation, weighting variants by their estimated degrees of dysfunction using VAAST. The top two genes across the genome were ATM (p &lt; 1e-7) and BRCA2 (p = 2e-5). We also observed nominally significant association signals in multiple genes of a priori interest, including STK11 (p = 0.004), TP53 (p = 0.016), and PALB2 (p = 0.032). To better characterize the contribution of rare genetic variation to PDAC risk, we evaluated rare variant effect sizes according to a variety of functional classifications in established susceptibility genes. In contrast to previous reports, our results suggest that truncating variants in ATM (nonsense SNVs, frameshift INDELs, and splicing SNVs) confer a very high risk of PDAC, with an OR of 34 (95% CI: 5.5-1400). Unlike in other ATM-associated cancers, variants of uncertain significance (VUS) predicted to be functionally impactful exhibited attenuated effect sizes relative to truncating variants, with an OR of only 1.8 (95% CI: 1.3-2.6). Effect sizes for truncating and known pathogenic variants in BRCA2 and PALB2 were largely consistent with previous reports, with ORs of 4.0 in both genes (95% CIs: 1.9 to 8.4 and 1.0 to 19, respectively). In TP53, we observed that VUSs exhibited an elevated risk for PDAC, irrespective of predicted functional severity (OR: 3.4, 95% CI: 1.1-11). We also conducted an initial assessment of copy number variants influencing PDAC risk using XHMM, identifying four CNVs of interest among cases and zero in controls: two partial gene duplications in ATM, one partial gene duplication in STK11, and one 12 gene duplication encompassing STK11. Additionally, we observed that relatives of truncation and pathogenic missense variants carriers in ATM were more significantly more likely to develop breast cancer, colon cancer, and Hodgkin disease, while relatives of TP53 variants carriers were enriched for numerous cancer types (1.3- to 125-fold increase in cancer risk compared to non-carriers). We also report association evidence for novel candidate genes and estimates for the contribution of familial relative risk from each gene of interest. Our study provides new insights into the genetic susceptibility of pancreatic cancer and highlight the under-appreciated role of VUSs in multiple susceptibility genes as well as the prominent importance of ATM truncating variants in PDAC risk.

Citation Format: Paul Scheet, Yao Yu, Kyle Chang, Michelle Hildebrandt, Jenny Permuth, Donghui Li, Chad Huff. Whole exome sequencing case-control study implicates truncating variants in ATM as major risk factors in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3397.