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Nat Commun. 2017 Mar 8;8:14674. doi: 10.1038/ncomms14674.

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

Author information

1
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
2
Department of Human Genetics, KU Leuven and University Hospitals Leuven, Herestraat 49, Box 602, B-3000 Leuven, Belgium.
3
Sarcoma Center, Western German Cancer Center, University of Duisburg-Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany.
4
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
5
Department of Pathology, Knight Cancer Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
6
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
7
Department of Pathology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, California 94305, USA.
8
Ludwig Center at Harvard, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
9
Portland VA Health Care System, Knight Cancer Institute, Oregon Health and Science University, 3181 Soutwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
10
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 75 Francis Street, Boston, Massachusetts 02115, USA.

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.

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