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

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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.

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Guo, Y. A., Chang, M. M., Huang, W., Ooi, W. F., Xing, M., Tan, P., & Skanderup, A. J. (2018). Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-03828-2

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