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

Yu Amanda Guo, Mei Mei Chang, Weitai Huang, Wen Fong Ooi, Manjie Xing, Patrick Tan () and Anders Jacobsen Skanderup ()
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Yu Amanda Guo: Genome Institute of Singapore
Mei Mei Chang: Genome Institute of Singapore
Weitai Huang: Genome Institute of Singapore
Wen Fong Ooi: Genome Institute of Singapore
Manjie Xing: Genome Institute of Singapore
Patrick Tan: Duke-NUS Medical School
Anders Jacobsen Skanderup: Genome Institute of Singapore

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03828-2

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