Abstract 5355: Multiple mutations to the same gene are selected for and cooperate to drive cancer

Abstract

Abstract Cancers accumulate oncogenic mutations whose biochemical impact depends upon other germline and somatic variants in the cell. It stands to reason that the consequence of a somatic mutation is mediated by the presence of additional genetic variants within the same gene, and by the allele on which they arise. We have undertaken integrative analyses of 27,534 human tumors, including 19,640 prospectively sequenced advanced and metastatic cancers, and revealed a startling rate of multiple non-synonymous somatic mutations in the same cancer gene and tumor, hereafter referred to as multiple mutations. Overall, 26% of primary and metastatic tumors had at least one cancer gene with two or more somatic mutations. A minority of multiple mutations arose from somatic hypermutation or as secondary mutations driving resistance to molecularly targeted therapy. Clonality analysis further indicated that the majority of multiple mutations were present in the same cell. Multiple cancer genes were enriched for a greater burden of multiple mutations than would be expected in the absence of selection, including APC, B2M, EGFR, and TERT. The allelic configuration of these mutations indicated that while multiple mutations in trans arose predominantly in tumor suppressor genes, consistent with the selective pressure for biallelic inactivation, the majority of phaseable mutations arose in cis in both tumor suppressors and oncogenes, implying a selective pressure exists for a biochemical function distinct from individual driver mutations in the same gene. Collectively, these data argue that multiple genetic variants within a gene and their allelic configurations can interact to drive cancers. Citation Format: Alexander N. Gorelick, Ed Reznik, Yanyan Cai, Craig Bielski, Chaitanya Bandlamudi, Alexander Penson, Philip Jonsson, Konnor La, Maurizio Scaltriti, Nikolaus Schultz, Barry S. Taylor. Multiple mutations to the same gene are selected for and cooperate to drive cancer [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 5355.