title: MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Inga-Marie
authors.initials: IM
authors.lastname: Schaefer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Yuexiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Cher-Wei
authors.initials: CW
authors.lastname: Liang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Nacef
authors.initials: N
authors.lastname: Bahri
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.|Department of Human Genetics, KU Leuven and University Hospitals Leuven, Herestraat 49, Box 602, B-3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Quattrone
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Leona
authors.initials: L
authors.lastname: Doyle
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Mariño-Enríquez
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lauria
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Meijun
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Human Genetics, KU Leuven and University Hospitals Leuven, Herestraat 49, Box 602, B-3000 Leuven, Belgium.
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.affiliation: Sarcoma Center, Western German Cancer Center, University of Duisburg-Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grunewald
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Jaclyn F
authors.initials: JF
authors.lastname: Hechtman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Armelle
authors.initials: A
authors.lastname: Dufresne
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Pathology, Knight Cancer Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Beadling
authors.affiliation: Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Ewa T
authors.initials: ET
authors.lastname: Sicinska
authors.affiliation: Department of Pathology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, California 94305, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.affiliation: Ludwig Center at Harvard, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Pathology, Knight Cancer Institute, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Portland VA Health Care System, Knight Cancer Institute, Oregon Health and Science University, 3181 Soutwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Chandrajit P
authors.identifier: 0000-0001-7297-3221
authors.initials: CP
authors.lastname: Raut
authors.affiliation: Sarcoma Center, Western German Cancer Center, University of Duisburg-Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, Massachusetts 02115, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D000073658:Loss of Function Mutation; D008297:Male; D025542:Neurofibromin 1 / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C499330:MAX protein, human; D025542:Neurofibromin 1; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha