Abstract 1279: Passenger mutation landscape in cancer genomes

Cancer progression is an evolutionary process during which thousands of somatic variants are accumulated within an individual. In the classic view of cancer progression, a handful of driver variants are thought to give a positive selection advantage to the cancer cell. The remaining variants, termed passengers, represent the overwhelming majority of the variants in cancer genomes, and their functional consequences are poorly understood. Furthermore, the bulk of these passengers fall within noncoding regions of the genome, making these the main product of whole-genome sequencing of tumors. In this work, we explore the functional landscape of passenger variants in various cancer cohorts by leveraging extensive pan-cancer variant calls from ~2500 uniformly processed whole cancer genomes. More specifically, we integrate their annotations and predicted functional impact scores to quantify the overall burdening of various elements in cancer genomes. We show that disruption of genetic regulatory elements in the noncoding genome correlates with altered gene expression. Furthermore, we also show how overall functional burdening of various genomic elements correlate with patient survival time, and tumor clonality. Finally, we observe statistical signals consistent with the notion that aggregated subsets of passenger variants - particularly those we predict to be functionally impactful- might confer weak selective effects. Citation Format: Sushant Kumar, Jonathan Warrel, Patrick Mcgillivray, William Meyerson, Shantao Li, Leonidas Salichos, Arif Harmanci, Alexander Fundichely, Calvin Chan, Carl Herrmann, Morten Nielsen, Lucas Lochovsky, Yan Zhang, Xiaotong Li, Ekta Khurana, Gad Getz, Mark Gerstein. Passenger mutation landscape in cancer genomes [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 1279.