Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers.

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Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers.

Nat Commun. 2018 Apr 18;9(1):1520

Authors: Guo YA, Chang MM, Huang W, Ooi WF, Xing M, Tan P, Skanderup AJ

Abstract
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs). These CBS hotspots remain significant even after controlling for a genome-wide elevated mutation rate at CBSs. In 3 out of 4 tested CBS hotspots, mutations are nominally associated with expression change of neighboring genes. CBS hotspot mutations are enriched in tumors showing chromosomal instability, co-occur with neighboring chromosomal aberrations, and are common in gastric (25%) and colorectal (19%) tumors but rare in other cancer types. Mutational disruption of specific CBSs may thus represent a tissue-specific mechanism of tumorigenesis conserved across gastrointestinal cancers.

PMID: 29670109 [PubMed - in process]

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