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Mismatch-repair signature mutations activate gene enhancers across colorectal cancer epigenomes

By Stevephen Hung, Alina Saiakhova, Zachary Faber, Cynthia F. Bartels, Devin Neu, Ian Bayles, Evelyn Ojo, Ellen S. Hong, W. Dean Pontius, Andrew R. Morton, Ruifu Liu, Matthew Kalady, David N. Wald, Sanford Markowitz, Peter C. Scacheri

Posted 07 Sep 2018
bioRxiv DOI: 10.1101/411264 (published DOI: 10.7554/eLife.40760)

Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. Our results suggest that MMR signature mutations activate or augment enhancers in CRC tumor epigenomes to provide a selective advantage.

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