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Mutational landscape and significance across 12 major cancer types

Author

Listed:
  • Cyriac Kandoth

    (The Genome Institute, Washington University in St Louis)

  • Michael D. McLellan

    (The Genome Institute, Washington University in St Louis)

  • Fabio Vandin

    (Brown University)

  • Kai Ye

    (The Genome Institute, Washington University in St Louis
    Washington University in St Louis)

  • Beifang Niu

    (The Genome Institute, Washington University in St Louis)

  • Charles Lu

    (The Genome Institute, Washington University in St Louis)

  • Mingchao Xie

    (The Genome Institute, Washington University in St Louis)

  • Qunyuan Zhang

    (The Genome Institute, Washington University in St Louis
    Washington University in St Louis)

  • Joshua F. McMichael

    (The Genome Institute, Washington University in St Louis)

  • Matthew A. Wyczalkowski

    (The Genome Institute, Washington University in St Louis)

  • Mark D. M. Leiserson

    (Brown University)

  • Christopher A. Miller

    (The Genome Institute, Washington University in St Louis)

  • John S. Welch

    (Washington University in St Louis
    Siteman Cancer Center, Washington University in St Louis)

  • Matthew J. Walter

    (Washington University in St Louis
    Siteman Cancer Center, Washington University in St Louis)

  • Michael C. Wendl

    (The Genome Institute, Washington University in St Louis
    Washington University in St Louis
    Washington University in St Louis)

  • Timothy J. Ley

    (The Genome Institute, Washington University in St Louis
    Washington University in St Louis
    Washington University in St Louis
    Siteman Cancer Center, Washington University in St Louis)

  • Richard K. Wilson

    (The Genome Institute, Washington University in St Louis
    Washington University in St Louis
    Siteman Cancer Center, Washington University in St Louis)

  • Benjamin J. Raphael

    (Brown University)

  • Li Ding

    (The Genome Institute, Washington University in St Louis
    Washington University in St Louis
    Washington University in St Louis
    Siteman Cancer Center, Washington University in St Louis)

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.

Suggested Citation

  • Cyriac Kandoth & Michael D. McLellan & Fabio Vandin & Kai Ye & Beifang Niu & Charles Lu & Mingchao Xie & Qunyuan Zhang & Joshua F. McMichael & Matthew A. Wyczalkowski & Mark D. M. Leiserson & Christop, 2013. "Mutational landscape and significance across 12 major cancer types," Nature, Nature, vol. 502(7471), pages 333-339, October.
  • Handle: RePEc:nat:nature:v:502:y:2013:i:7471:d:10.1038_nature12634
    DOI: 10.1038/nature12634
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    Cited by:

    1. M. G. Filippone & D. Gaglio & R. Bonfanti & F. A. Tucci & E. Ceccacci & R. Pennisi & M. Bonanomi & G. Jodice & M. Tillhon & F. Montani & G. Bertalot & S. Freddi & M. Vecchi & A. Taglialatela & M. Roma, 2022. "CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Mu-Kuei Shieu & Hsin-Yu Ho & Shu-Hui Lin & Yu-Sheng Lo & Chia-Chieh Lin & Yi-Ching Chuang & Ming-Ju Hsieh & Mu-Kuan Chen, 2022. "Association of KMT2C Genetic Variants with the Clinicopathologic Development of Oral Cancer," IJERPH, MDPI, vol. 19(7), pages 1-10, March.
    3. Emilien Nicolas & Paul Simion & Marc Guérineau & Matthieu Terwagne & Mathilde Colinet & Julie Virgo & Maxime Lingurski & Anaïs Boutsen & Marc Dieu & Bernard Hallet & Karine Doninck, 2023. "Horizontal acquisition of a DNA ligase improves DNA damage tolerance in eukaryotes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Yanling Liu & Jonathon Klein & Richa Bajpai & Li Dong & Quang Tran & Pandurang Kolekar & Jenny L. Smith & Rhonda E. Ries & Benjamin J. Huang & Yi-Cheng Wang & Todd A. Alonzo & Liqing Tian & Heather L., 2023. "Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Irina Ostrovnaya & Audrey Mauguen & Venkatraman E. Seshan & Colin B. Begg, 2021. "Testing tumors from different anatomic sites for clonal relatedness using somatic mutation data," Biometrics, The International Biometric Society, vol. 77(1), pages 283-292, March.

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