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MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation

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Listed:
  • Inga-Marie Schaefer

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Yuexiang Wang

    (Brigham and Women’s Hospital, Harvard Medical School
    Present address: Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU);Key Laboratory of Stem Cell Biology, Institute of Health Sciences, SIBS, Chinese Academy of Sciences, Shanghai JiaoTong University School of Medicine; Collaborative Innovation Center of Systems Biomedicine, 320 Yueyang Road, Shanghai 200025, China)

  • Cher-wei Liang

    (Brigham and Women’s Hospital, Harvard Medical School
    Present address: Department and Graduate Institute of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, 7 Zhong-Shan South Road, Taipei, Taiwan 10002)

  • Nacef Bahri

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Anna Quattrone

    (Brigham and Women’s Hospital, Harvard Medical School
    KU Leuven and University Hospitals Leuven)

  • Leona Doyle

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Adrian Mariño-Enríquez

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Alexandra Lauria

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Meijun Zhu

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Maria Debiec-Rychter

    (KU Leuven and University Hospitals Leuven)

  • Susanne Grunewald

    (Sarcoma Center, Western German Cancer Center, University of Duisburg-Essen Medical School)

  • Jaclyn F. Hechtman

    (Memorial Sloan-Kettering Cancer Center)

  • Armelle Dufresne

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Cristina R. Antonescu

    (Memorial Sloan-Kettering Cancer Center)

  • Carol Beadling

    (Knight Cancer Institute, Oregon Health and Science University)

  • Ewa T. Sicinska

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • Matt van de Rijn

    (Stanford University Medical Center)

  • George D. Demetri

    (Ludwig Center at Harvard, Dana-Farber Cancer Institute)

  • Marc Ladanyi

    (Memorial Sloan-Kettering Cancer Center)

  • Christopher L. Corless

    (Knight Cancer Institute, Oregon Health and Science University)

  • Michael C. Heinrich

    (Portland VA Health Care System, Knight Cancer Institute, Oregon Health and Science University)

  • Chandrajit P. Raut

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Sebastian Bauer

    (Sarcoma Center, Western German Cancer Center, University of Duisburg-Essen Medical School)

  • Jonathan A. Fletcher

    (Brigham and Women’s Hospital, Harvard Medical School)

Abstract

KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.

Suggested Citation

  • Inga-Marie Schaefer & Yuexiang Wang & Cher-wei Liang & Nacef Bahri & Anna Quattrone & Leona Doyle & Adrian Mariño-Enríquez & Alexandra Lauria & Meijun Zhu & Maria Debiec-Rychter & Susanne Grunewald & , 2017. "MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation," Nature Communications, Nature, vol. 8(1), pages 1-6, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14674
    DOI: 10.1038/ncomms14674
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    Cited by:

    1. Benjamin A. Nacev & Francisco Sanchez-Vega & Shaleigh A. Smith & Cristina R. Antonescu & Evan Rosenbaum & Hongyu Shi & Cerise Tang & Nicholas D. Socci & Satshil Rana & Rodrigo Gularte-Mérida & Ahmet Z, 2022. "Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Feifei Xie & Shuzhen Luo & Dongbing Liu & Xiaojing Lu & Ming Wang & Xiaoxiao Liu & Fujian Jia & Yuzhi Pang & Yanying Shen & Chunling Zeng & Xinli Ma & Daoqiang Tang & Lin Tu & Linxi Yang & Yumei Cheng, 2024. "Genomic and transcriptomic landscape of human gastrointestinal stromal tumors," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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