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

• Published in: Nature communications Vol. 9; no. 1; pp. 1520 - 14
• Main Authors: Guo, Yu Amanda, Chang, Mei Mei, Huang, Weitai, Ooi, Wen Fong, Xing, Manjie, Tan, Patrick, Skanderup, Anders Jacobsen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 631/67/1504/1829; 631/67/69; Binding Sites; Cancer; CCCTC-Binding Factor - genetics; Cell Line, Tumor; Chromosomal Instability; Chromosome Aberrations; Conserved Sequence; Databases, Genetic; DNA Mutational Analysis; Epigenesis, Genetic; False Positive Reactions; Gastric cancer; Gastrointestinal Neoplasms - genetics; Gene expression; Gene Expression Profiling; Genes; Genome, Human; Genomes; Genomic instability; Genomics; Humanities and Social Sciences; Humans; INDEL Mutation; Mathematical models; Models, Statistical; multidisciplinary; Mutation; Mutation hot spots; Mutation Rate; Science; Science (multidisciplinary); Stability; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• 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. The impact of non-coding somatic mutations in gastric cancer is unknown. Here, using whole genome sequencing data from 212 gastric tumors, the authors identify recurring mutations at specific CTCF binding sites that are common across gastrointestinal cancers and associated with chromosomal instability.