title: Genome-wide analysis of noncoding regulatory mutations in cancer.
abstract: Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes.
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: 1] Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Jacobsen
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: 1] Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: William
authors.identifier: 0000000195824413
authors.initials: W
authors.lastname: Lee
mesh_terms: D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D006801:Humans; D058977:Molecular Sequence Annotation; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics; D019098:Telomerase / Q000235:genetics
chemical_list: C491545:SDHD protein, human; D013385:Succinate Dehydrogenase; C509186:TERT protein, human; D019098:Telomerase