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 Marinõ-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 Corless & 4 others Michael Heinrich, Chandrajit P. Raut, Sebastian Bauer, Jonathan A. Fletcher

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Article number14674
JournalNature Communications
Volume8
DOIs
StatePublished - Mar 8 2017

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Gastrointestinal Stromal Tumors
Cell proliferation
deactivation
Tumors
tumors
Cell Proliferation
mutations
deletion
Foster Home Care
chromosomes
Chromosomes
progressions
Mutation
Chromosome Deletion
Sequence Deletion
genes
Hyperplasia
induction
Cell Cycle
coding

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Schaefer, I. M., Wang, Y., Liang, C. W., Bahri, N., Quattrone, A., Doyle, L., ... Fletcher, J. A. (2017). MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nature Communications, 8, [14674]. https://doi.org/10.1038/ncomms14674

MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. / Schaefer, Inga Marie; Wang, Yuexiang; Liang, Cher Wei; Bahri, Nacef; Quattrone, Anna; Doyle, Leona; Marinõ-Enríquez, Adrian; Lauria, Alexandra; Zhu, Meijun; Debiec-Rychter, Maria; Grunewald, Susanne; Hechtman, Jaclyn F.; Dufresne, Armelle; Antonescu, Cristina R.; Beadling, Carol; Sicinska, Ewa T.; Van De Rijn, Matt; Demetri, George D.; Ladanyi, Marc; Corless, Christopher; Heinrich, Michael; Raut, Chandrajit P.; Bauer, Sebastian; Fletcher, Jonathan A.

In: Nature Communications, Vol. 8, 14674, 08.03.2017.

Research output: Contribution to journalArticle

Schaefer, IM, Wang, Y, Liang, CW, Bahri, N, Quattrone, A, Doyle, L, Marinõ-Enríquez, A, Lauria, A, Zhu, M, Debiec-Rychter, M, Grunewald, S, Hechtman, JF, Dufresne, A, Antonescu, CR, Beadling, C, Sicinska, ET, Van De Rijn, M, Demetri, GD, Ladanyi, M, Corless, C, Heinrich, M, Raut, CP, Bauer, S & Fletcher, JA 2017, 'MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation', Nature Communications, vol. 8, 14674. https://doi.org/10.1038/ncomms14674
Schaefer, Inga Marie ; Wang, Yuexiang ; Liang, Cher Wei ; Bahri, Nacef ; Quattrone, Anna ; Doyle, Leona ; Marinõ-Enríquez, Adrian ; Lauria, Alexandra ; Zhu, Meijun ; Debiec-Rychter, Maria ; Grunewald, Susanne ; Hechtman, Jaclyn F. ; Dufresne, Armelle ; Antonescu, Cristina R. ; Beadling, Carol ; Sicinska, Ewa T. ; Van De Rijn, Matt ; Demetri, George D. ; Ladanyi, Marc ; Corless, Christopher ; Heinrich, Michael ; Raut, Chandrajit P. ; Bauer, Sebastian ; Fletcher, Jonathan A. / MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. In: Nature Communications. 2017 ; Vol. 8.
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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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AU - Marinõ-Enríquez, Adrian

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AU - Sicinska, Ewa T.

AU - Van De Rijn, Matt

AU - Demetri, George D.

AU - Ladanyi, Marc

AU - Corless, Christopher

AU - Heinrich, Michael

AU - Raut, Chandrajit P.

AU - Bauer, Sebastian

AU - Fletcher, Jonathan A.

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