Mismatch repair-signature mutations activate gene enhancers across human colorectal cancer epigenomes
2019
Stevephen Hung | Alina Saiakhova | Zachary J Faber | Cynthia F Bartels | Devin Neu | Ian Bayles | Evelyn Ojo | Ellen S Hong | W Dean Pontius | Andrew R Morton | Ruifu Liu | Matthew F Kalady | David N Wald | Sanford Markowitz | Peter C Scacheri
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 enhancers in CRC tumor epigenomes to provide a selective advantage.
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