RT Journal Article
SR Electronic
T1 Motif Disruption Domains Lead To Cancer Gene Expression Rewiring
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 126359
DO 10.1101/126359
A1 Fabien C. Lamaze
A1 Aurelien Chateigner
A1 Hilary A. Edgington
A1 Marie-Julie Fave
A1 Armande Ang Houle
A1 PCAWG3
A1 Philip Awadalla
YR 2017
UL http://biorxiv.org/content/early/2017/04/11/126359.abstract
AB Somatic mutations accumulate in non-coding regions of the genome during tumorigenesis, but their functional characterization presents a challenge. Somatic non-coding mutations rarely overlap among patients, which necessitates large sample sizes to detect associations. We analysed somatic mutations called from whole-genome sequencing (WGS) and RNA sequencing (RNAseq) from 3000 tumors across the Pan-Cancer Analysis of Whole Genomes to identify and functionally characterize mutation accumulation and its impact on gene dysregulation in cancer. We identified 1.5 million motif disruption domains (MDDs) across 40 cancer types, which we characterized as pan-cancer targets for recurrent mutation accumulation. These MDDs deregulate gene expression in cancer-specific and pan-cancer patterns by disrupting transcription factor binding sites in regulatory and insulator elements. Disruption is most recurrent across individuals at MDDs in conserved open chromatin, revealing potential drivers. This accumulation of somatic variants targeting regulatory and structural elements in MDDs generates gene expression dysregulation during tumorigenesis.MDDMotif Disruption DomainPCAWGthe Pan-Cancer Analysis of Whole Genomes projectSNVSomatic single Nucleotide VariantsTFBSTranscription Factor Binding Site