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

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, Jaclyn F. Hechtman, Armelle Dufresne, Cristina R. Antonescu, Carol Beadling, Ewa T. Sicinska, Matt van de Rijn, George D. Demetri, Marc Ladanyi, Christopher L. Corless, Michael C. Heinrich, Chandrajit P. Raut, Sebastian Bauer and Jonathan A. Fletcher ()
Additional contact information
Inga-Marie Schaefer: Brigham and Women’s Hospital, Harvard Medical School
Yuexiang Wang: Brigham and Women’s Hospital, Harvard Medical School
Cher-wei Liang: Brigham and Women’s Hospital, Harvard Medical School
Nacef Bahri: Brigham and Women’s Hospital, Harvard Medical School
Anna Quattrone: Brigham and Women’s Hospital, Harvard Medical School
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

Nature Communications, 2017, vol. 8, issue 1, 1-6

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14674

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