Abstract 3270: Pan-cancer analysis of 1,962 whole-genomes reveals significantly mutated CTCF/cohesin insulators

Abstract

Recent studies have shown that mutations at non-coding elements, such as the TERT promoter and ESR1 enhancer, can act as cancer drivers. However, an important class of non-coding elements, namely CTCF/cohesin insulators, has been overlooked in the previous driver analyses. It is known that promoter and enhancer interactions are facilitated by partitioning of the human genome into DNA loops. These loops act as insulated neighborhoods preventing the interactions of enhancers and promoters across loops. They are held together by the binding of two CCCTCF binding factors (CTCF) and the cohesin complex, which consists of four core transcription factor subunits (SMC1, SMC3, RAD21 and either STAG2 or STAG1) at the loop ends. Disruption of the loop anchor regions, called CTCF/cohesin insulators, can lead to de novo enhancer-promoter interactions and subsequent dysregulation of associated genes. We used insulator annotations from cohesin ChIA-PET assays and analyzed somatic mutations in 1,962 whole-genomes from 21 cancer types. We find that the mutations predicted to disrupt DNA binding motifs of CTCF, RAD21 and SMC3 are enriched in many cancer types due to the sequence contexts of neutral mutational processes. Using a novel computational approach, CNCDriver (Cornell Non-Coding Driver), that balances the interplay between neutral mutational rate covariates of CTCF/RAD21/SMC3 motif loss and the stronger functional impact of motif-disrupting mutations, we identify the insulators that show signals of positive selection during tumor evolution. We find that the mutations in significantly mutated insulators are associated with differential expression of genes involved in multiple cancer pathways: TGF-β, Hedgehog and Wnt signaling. In particular, we find 16% of melanoma samples show mutations in an insulator that are associated with up-regulation of TGFB1, which is known to promote angiogenesis and tumor cell migration in melanoma. Thus, our study reveals insulators as a novel class of non-coding cancer drivers. Identification of significantly mutated insulators can complement the identification of other types of non-coding cancer drivers (promoters, enhancers and ncRNAs) to fully understand the role of non-coding alterations in tumorigenesis. Citation Format: Eric Minwei Liu, Alexander Martinez-Fundichely, Tawny Cuykendall, Jason G. Dumelie, Matthew MacKay, Priyanka Dhingra, Samie R. Jaffrey, Ekta Khurana. Pan-cancer analysis of 1,962 whole-genomes reveals significantly mutated CTCF/cohesin insulators [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 3270.