Abstract B2-42: Systematic dissection of multi-scale mutational hotspots across 21 cancer types reveals a rich landscape of functionally targeted oncogenic disruptions
Authors: Araya Carlos Luis , Cenik Can , Reuter Jason , Snyder Michael , Greenleaf William 
Published: May 2016

Abstract
Targeted exome sequencing across dozens of tumor types has led to the discovery of critical cancer-driver genes providing invaluable insight into the genetics and cell biology of cancer. However, most existing approaches are aimed at identifying protein-disrupting mutations alone and hence ignore ~45% of exome variant calls that fall outside of coding regions. Despite clear examples of import of non-coding mutations to specific diseases (such as recurrent mutations in the TERT promoter in melanoma), analyses of non-coding oncogenic alterations have been limited to a small subset of tumor types or have been performed across cancer-types (pan-cancer). Moreover, these analyses have employed either annotation-guided or fixed size sliding-window approaches that presume the relevant scale of functional elements altered in cancer. Here, we employed spatial clustering methods for multi-scale, unbiased detection of significantly mutated regions (SMRs) in 21 tumor types. Using data from &gt;4,700 exomes, we uncovered a diversity of functional genomic elements (ranging from 1 bp to ≥1 kb) frequently disrupted in protein coding and novel, exon-proximal, non-coding features, including regions within 5' UTRs and promoters that are affected in up to ~18% of specific tumor-types. We identified functional associations between SMRs and changes in signalling pathways as determined from RPPA experiments. SMRs allowed us to explore substructure in the distribution of mutations within cancer-driver genes. This analysis revealed that PI3Kα is densely, but differentially mutated in distinct tumor types, and highlights a novel region recurrently disrupted within this well studied oncogene. Mapping coding SMRs to the molecular structures of ~180 proteins permitted a high-resolution interrogation of protein-protein interfaces altered in cancer and the detection of SMRs spatially clustered within protein structures. Coding SMRs disrupt numerous sites of post-translational modification and transcription factor binding, and are associated with alterations to transcriptional profiles as determined by RNA-seq. Surprisingly, we detect an SMR within NFE2L2 that leads to concordant, large-scale transcriptional changes in distinct cancer types. Finally, our results suggest candidate epitopes for immunotherapy and highlight valuable opportunities in reanalyzing the vast repertoire of exome data acquired to date.
Note: This abstract was not presented at the conference.
Citation Format: Carlos Luis Araya, Can Cenik, Jason Reuter, Michael Snyder, William Greenleaf. Systematic dissection of multi-scale mutational hotspots across 21 cancer types reveals a rich landscape of functionally targeted oncogenic disruptions. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-42.