title: Chromatin accessibility contributes to simultaneous mutations of cancer genes.
abstract: Somatic mutations of many cancer genes tend to co-occur (termed co-mutations) in certain patterns during tumor initiation and progression. However, the genetic and epigenetic mechanisms that contribute to the co-mutations of these cancer genes have yet to be explored. Here, we systematically investigated the association between the somatic co-mutations of cancer genes and high-order chromatin conformation. Significantly, somatic point co-mutations in protein-coding genes were closely associated with high-order spatial chromatin folding. We propose that these regions be termed Spatial Co-mutation Hotspots (SCHs) and report their occurrence in different cancer types. The conserved mutational signatures and DNA sequences flanking these point co-mutations, as well as CTCF-binding sites, are also enriched within the SCH regions. The genetic alterations that are harboured in the same SCHs tend to disrupt cancer driver genes involved in multiple signalling pathways. The present work demonstrates that high-order spatial chromatin organisation may contribute to the somatic co-mutations of certain cancer genes during tumor development.
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Xian-Bin
authors.initials: XB
authors.lastname: Su
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Kun-Yan
authors.initials: KY
authors.lastname: He
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiaotong University, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Bing-Hao
authors.initials: BH
authors.lastname: Wu
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Bo-Yu
authors.initials: BY
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiaotong University, Shanghai, China.|Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China.
authors.forename: Ze-Guang
authors.initials: ZG
authors.lastname: Han
mesh_terms: D000076246:CCCTC-Binding Factor / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry* / Q000648:ultrastructure; D042002:Chromatin Assembly and Disassembly; D018450:Disease Progression; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes; D011485:Protein Binding; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D002843:Chromatin