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

Nat Commun. 2018 Apr 18;9(1):1520. doi: 10.1038/s41467-018-03828-2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CCCTC-Binding Factor / genetics*
  • Cell Line, Tumor
  • Chromosomal Instability*
  • Chromosome Aberrations
  • Conserved Sequence
  • DNA Mutational Analysis*
  • Databases, Genetic
  • Epigenesis, Genetic
  • False Positive Reactions
  • Gastrointestinal Neoplasms / genetics*
  • Gene Expression Profiling
  • Genome, Human
  • Genomics
  • Humans
  • INDEL Mutation*
  • Models, Statistical
  • Mutation Rate
  • Mutation*


  • CCCTC-Binding Factor
  • CTCF protein, human