title: Mutational landscape and significance across 12 major cancer types.
abstract: The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Cyriac
authors.initials: C
authors.lastname: Kandoth
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Vandin
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Ye
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Beifang
authors.initials: B
authors.lastname: Niu
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Xie
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Qunyuan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: McMichael
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wyczalkowski
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Mark D M
authors.initials: MDM
authors.lastname: Leiserson
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Medicine, Washington University in St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, Missouri 63108, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.affiliation: Department of Medicine, Washington University in St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St Louis, Missouri 63108, USA.|Department of Mathematics, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wendl
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
authors.affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.|Department of Genetics, Washington University in St Louis, Missouri 63108, USA.|Department of Medicine, Washington University in St Louis, Missouri 63108, USA.|Siteman Cancer Center, Washington University in St Louis, Missouri 63108, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases