Abstract 729: Zygosity, lineage, and penetrance dictate the role of germline pathogenicity in tumorigenesis
Authors: Bandlamudi Chaitanya , Srinivasan Preethi , Jonsson Philip , Kemel Yelena M. , Chavan Shweta S. , Richards Allison L. , Penson Alex , Bielski Craig M. , Fong Chris , Syed Aijazuddin , Jayakumaran Gowtham , Prasad Meera , Hwee Jason , Schultz Nikolaus , Mukherjee Semanti , Joseph Vijai , Mandelkar Diana , Birsoy Ozge , Zhang Liying , Shia Jinru , Zehir Ahmet , Ladanyi Marc , Hyman David M. , Offit Kenneth , Robson Mark E. , Solit David B. , Stadler Zsofia K. , Berger Michael F. , Taylor Barry S. 
Published: August 2019

Abstract
Human cancers arise from environmental, heritable, and somatic factors. While each has been studied extensively, how these factors interact to drive tumorigenesis and disease phenotypes is poorly understood. Here, we integrated germline pathogenicity with somatic alterations inferred from the prospective sequencing of 17,152 advanced cancer patients across 55 cancer types to explore their interplay in tumorigenesis. Leveraging expert curated germline variant calls from 5,358 patients, we developed a combined machine learning and risk stratification-based approach for pathogenicity assessment. Overall, 10.3% of patients harbored a pathogenic allele with penetrance levels ranging from high to low, and an additional 6.3% with a variant of uncertain penetrance. Integrating high-precision zygosity inference in the concomitant cancer diagnoses, we found that only carriers of high penetrance germline pathogenic alleles that are biallelically inactivated in their tumors had an earlier age of onset (51y in carriers vs. 58y in germline WT, p-value=3.5e-12), and an elevated rate of multiple independent cancer diagnoses (23% in carriers vs 13% in germline WT, p-value=1.6e-7). Broadly, penetrance dictated somatic dependence, with only those higher penetrant germline pathogenic alleles associated with lineage-dependent selective pressure for somatic biallelic inactivation (p-value&lt;2e-16). Tumor lineage dictated the substantial variability in the rate of tumor-specific biallelic inactivation of germline alleles, even among high penetrance genes. Among only high and moderate penetrance genes, high-risk cancers for which these alleles predispose and are therefore strongly associated by prevalence had the highest biallelic inactivation rates as compared to those for which no association exists (85 versus 30%, respectively; p-value&lt;2e-16). Consequently, nearly 30% of all tumors diagnosed in carriers of high penetrance germline alleles are likely sporadic cancers whose tumorigenesis is unrelated to the germline dysfunction. Moreover, tumorigenesis in only those carriers of high penetrance germline alleles biallelically inactivated in their tumors required fewer somatic oncogenic driver mutations overall to confer a selective growth advantage, emphasizing their distinct role as a founding event in disease pathogenesis. Collectively, the role of germline pathogenicity in tumorigenesis is determined by penetrance and zygosity in a manner that is lineage-dependent, thereby facilitating the discovery of true germline drivers and multiple distinct routes to tumorigenesis in affected patients, with implications for disease pathogenesis, screening, and ultimately therapy.
Citation Format: Chaitanya Bandlamudi, Preethi Srinivasan, Philip Jonsson, Yelena M. Kemel, Shweta S. Chavan, Allison L. Richards, Alex Penson, Craig M. Bielski, Chris Fong, Aijazuddin Syed, Gowtham Jayakumaran, Meera Prasad, Jason Hwee, Nikolaus Schultz, Semanti Mukherjee, Vijai Joseph, Diana Mandelkar, Ozge Birsoy, Liying Zhang, Jinru Shia, Ahmet Zehir, Marc Ladanyi, David M. Hyman, Kenneth Offit, Mark E. Robson, David B. Solit, Zsofia K. Stadler, Michael F. Berger, Barry S. Taylor. Zygosity, lineage, and penetrance dictate the role of germline pathogenicity in tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 729.