Corces MR*, Granja JM*, Shams S, Louie BH, Seoane JA, Zhou W, Silva TC, Greoneveld C, Wong CK, Cho SW, Satpathy AT, Mumbach MR, Hoadley KA, Robertson AG, Sheffield NC, Felau I, Castro MAA, Berman BP, Staudt LM, Zenklusen JC, Laird PW, Curtis C, TCGA, Greenleaf WJ*, Chang HY*.
Science, 26 October 2018
We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible DNA elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-DNA footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy.