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Mutations of the BRAF gene in human cancer

Author

Listed:
  • Helen Davies

    (Wellcome Trust Genome Campus)

  • Graham R. Bignell

    (Wellcome Trust Genome Campus)

  • Charles Cox

    (Wellcome Trust Genome Campus)

  • Philip Stephens

    (Wellcome Trust Genome Campus)

  • Sarah Edkins

    (Wellcome Trust Genome Campus)

  • Sheila Clegg

    (Wellcome Trust Genome Campus)

  • Jon Teague

    (Wellcome Trust Genome Campus)

  • Hayley Woffendin

    (Wellcome Trust Genome Campus)

  • Mathew J. Garnett

    (Institute of Cancer Research)

  • William Bottomley

    (Wellcome Trust Genome Campus)

  • Neil Davis

    (Wellcome Trust Genome Campus)

  • Ed Dicks

    (Wellcome Trust Genome Campus)

  • Rebecca Ewing

    (Wellcome Trust Genome Campus)

  • Yvonne Floyd

    (Wellcome Trust Genome Campus)

  • Kristian Gray

    (Wellcome Trust Genome Campus)

  • Sarah Hall

    (Wellcome Trust Genome Campus)

  • Rachel Hawes

    (Wellcome Trust Genome Campus)

  • Jaime Hughes

    (Wellcome Trust Genome Campus)

  • Vivian Kosmidou

    (Wellcome Trust Genome Campus)

  • Andrew Menzies

    (Wellcome Trust Genome Campus)

  • Catherine Mould

    (Wellcome Trust Genome Campus)

  • Adrian Parker

    (Wellcome Trust Genome Campus)

  • Claire Stevens

    (Wellcome Trust Genome Campus)

  • Stephen Watt

    (Wellcome Trust Genome Campus)

  • Steven Hooper

    (Institute of Cancer Research)

  • Rebecca Wilson

    (Institute of Cancer Research)

  • Hiran Jayatilake

    (Institute of Cancer Research)

  • Barry A. Gusterson

    (University of Glasgow)

  • Colin Cooper

    (Institute of Cancer Research)

  • Janet Shipley

    (Institute of Cancer Research)

  • Darren Hargrave

    (Institute of Cancer Research)

  • Katherine Pritchard-Jones

    (Institute of Cancer Research)

  • Norman Maitland

    (University of York)

  • Georgia Chenevix-Trench

    (RBH Post Office Herston)

  • Gregory J. Riggins

    (Duke University Medical Centre)

  • Darell D. Bigner

    (Duke University Medical Centre)

  • Giuseppe Palmieri

    (Institute of Molecular Genetics, C.N.R)

  • Antonio Cossu

    (University of Sassari)

  • Adrienne Flanagan

    (Duke University Medical Centre
    Royal Free & University College Medical School)

  • Andrew Nicholson

    (Royal Brompton Hospital)

  • Judy W. C. Ho

    (The University of Hong Kong, Queen Mary Hospital)

  • Suet Y. Leung

    (The University of Hong Kong, Queen Mary Hospital)

  • Siu T. Yuen

    (The University of Hong Kong, Queen Mary Hospital)

  • Barbara L. Weber

    (University of Pennsylvania Cancer Center)

  • Hilliard F. Seigler

    (Duke University Medical Centre)

  • Timothy L. Darrow

    (Duke University Medical Centre)

  • Hugh Paterson

    (Institute of Cancer Research)

  • Richard Marais

    (Institute of Cancer Research)

  • Christopher J. Marshall

    (Institute of Cancer Research)

  • Richard Wooster

    (Wellcome Trust Genome Campus
    Institute of Cancer Research)

  • Michael R. Stratton

    (Wellcome Trust Genome Campus
    Institute of Cancer Research)

  • P. Andrew Futreal

    (Wellcome Trust Genome Campus)

Abstract

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS–RAF–MEK–ERK–MAP kinase pathway mediates cellular responses to growth signals1. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS1,2,3. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

Suggested Citation

  • Helen Davies & Graham R. Bignell & Charles Cox & Philip Stephens & Sarah Edkins & Sheila Clegg & Jon Teague & Hayley Woffendin & Mathew J. Garnett & William Bottomley & Neil Davis & Ed Dicks & Rebecca, 2002. "Mutations of the BRAF gene in human cancer," Nature, Nature, vol. 417(6892), pages 949-954, June.
    • Handle: RePEc:nat:nature:v:417:y:2002:i:6892:d:10.1038_nature00766
    DOI: 10.1038/nature00766
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    Citations

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    Cited by:

    1. Sony Malhotra & Ali F Alsulami & Yang Heiyun & Bernardo Montano Ochoa & Harry Jubb & Simon Forbes & Tom L Blundell, 2019. "Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census," PLOS ONE, Public Library of Science, vol. 14(7), pages 1-22, July.
    2. Eunyoung Park & Shaun Rawson & Anna Schmoker & Byeong-Won Kim & Sehee Oh & Kangkang Song & Hyesung Jeon & Michael J. Eck, 2023. "Cryo-EM structure of a RAS/RAF recruitment complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Chuan-Hsin Chang & Yue-Cune Chang, 2022. "Comparing the Therapeutic Efficacies of Lung Cancer: Network Meta-Analysis Approaches," IJERPH, MDPI, vol. 19(21), pages 1-20, November.
    4. Josefine Radke & Elisa Schumann & Julia Onken & Randi Koll & Güliz Acker & Bohdan Bodnar & Carolin Senger & Sascha Tierling & Markus Möbs & Peter Vajkoczy & Anna Vidal & Sandra Högler & Petra Kodajova, 2022. "Decoding molecular programs in melanoma brain metastases," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    5. Palistha Shrestha & Jeevan Kandel & Hilal Tayara & Kil To Chong, 2024. "Post-translational modification prediction via prompt-based fine-tuning of a GPT-2 model," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Jasmeen Oberoi & Xavi Aran Guiu & Emily A. Outwin & Pascale Schellenberger & Theodoros I. Roumeliotis & Jyoti S. Choudhary & Laurence H. Pearl, 2022. "HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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