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 L. Corless; Michael C. Heinrich; Chandrajit P. Raut; Sebastian Bauer; Jonathan A. Fletcher

doi:10.1038/ncomms14674

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 L. CorlessMichael C. Heinrich, Chandrajit P. Raut, Sebastian Bauer, Jonathan A. Fletcher

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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.

Original language	English (US)
Article number	14674
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14674
State	Published - Mar 8 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Schaefer, I. M., Wang, Y., Liang, C. W., Bahri, N., Quattrone, A., Doyle, L., Marinõ-Enríquez, A., Lauria, A., Zhu, M., Debiec-Rychter, M., Grunewald, S., Hechtman, J. F., Dufresne, A., Antonescu, C. R., Beadling, C., Sicinska, E. T., Van De Rijn, M., Demetri, G. D., Ladanyi, M., ... Fletcher, J. A. (2017). MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nature communications, 8, Article 14674. https://doi.org/10.1038/ncomms14674

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, CL , Heinrich, MC, 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

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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.",

author = "Schaefer, {Inga Marie} and Yuexiang Wang and Liang, {Cher Wei} and Nacef Bahri and Anna Quattrone and Leona Doyle and Adrian Marin{\~o}-Enr{\'i}quez and Alexandra Lauria and Meijun Zhu and Maria Debiec-Rychter and Susanne Grunewald and Hechtman, {Jaclyn F.} and Armelle Dufresne and Antonescu, {Cristina R.} and Carol Beadling and Sicinska, {Ewa T.} and {Van De Rijn}, Matt and Demetri, {George D.} and Marc Ladanyi and Corless, {Christopher L.} and Heinrich, {Michael C.} and Raut, {Chandrajit P.} and Sebastian Bauer and Fletcher, {Jonathan A.}",

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year = "2017",

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doi = "10.1038/ncomms14674",

language = "English (US)",

volume = "8",

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T1 - MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation

AU - Schaefer, Inga Marie

AU - Wang, Yuexiang

AU - Liang, Cher Wei

AU - Bahri, Nacef

AU - Quattrone, Anna

AU - Doyle, Leona

AU - Marinõ-Enríquez, Adrian

AU - Lauria, Alexandra

AU - Zhu, Meijun

AU - Debiec-Rychter, Maria

AU - Grunewald, Susanne

AU - Hechtman, Jaclyn F.

AU - Dufresne, Armelle

AU - Antonescu, Cristina R.

AU - Beadling, Carol

AU - Sicinska, Ewa T.

AU - Van De Rijn, Matt

AU - Demetri, George D.

AU - Ladanyi, Marc

AU - Corless, Christopher L.

AU - Heinrich, Michael C.

AU - Raut, Chandrajit P.

AU - Bauer, Sebastian

AU - Fletcher, Jonathan A.

PY - 2017/3/8

Y1 - 2017/3/8

N2 - 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.

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

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