Format

Send to

Choose Destination
Elife. 2019 Feb 13;8. pii: e40760. doi: 10.7554/eLife.40760.

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

Author information

1
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, United States.
2
Department of Pathology, Case Western Reserve University, Cleveland, United States.
3
Department of Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
4
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, United States.
5
Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, United States.
6
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, United States.
7
Department of Medicine, Case Western Reserve University, Cleveland, United States.

Abstract

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.

KEYWORDS:

cancer biology; cis-regulatory mutation; colorectal cancer; gene enhancer; genetics; genomics; human

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center