Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

被引：487

作者：

Buczkowicz, Pawel ^{[1
,2
,3
]}

Hoeman, Christine ^{[4
]}

Rakopoulos, Patricia ^{[2
,3
]}

Pajovic, Sanja ^{[2
]}

Letourneau, Louis ^{[5
]}

Dzamba, Misko ^{[6
]}

Morrison, Andrew ^{[2
]}

Lewis, Peter ^{[7
]}

Bouffet, Eric ^{[8
]}

Bartels, Ute ^{[8
]}

Zuccaro, Jennifer ^{[2
]}

Agnihotri, Sameer ^{[2
]}

Rya, Scott

Barszczyk, Mark ^{[2
,3
]}

Chornenkyy, Yevgen ^{[2
,3
]}

Bourgey, Mathieu ^{[5
]}

Bourque, Guillaume ^{[5
]}

Montpetit, Alexandre ^{[5
]}

Cordero, Francisco ^{[4
]}

Castelo-Branco, Pedro ^{[2
]}

Mangere, Joshua ^{[2
]}

Tabori, Uri ^{[2
,8
]}

Ching, King ^{[2
]}

Huang, Annie ^{[2
,8
]}

Taylor, Kathryn R. ^{[9
]}

Mackay, Alan ^{[9
]}

Bendell, Anne E. ^{[10
]}

Nazarian, Javad ^{[11
]}

Fangusaro, Jason R. ^{[12
]}

Karajannis, Matthias A. ^{[13
]}

Zagzag, David

Foreman, Nicholas K. ^{[14
]}

Donson, Andrew ^{[14
]}

Hegert, Julia V. ^{[15
]}

Smith, Amy ^{[15
]}

Chan, Jennifer ^{[16
]}

Lafay-Cousin, Lucy ^{[16
]}

Dunn, Sandra ^{[17
]}

Hukin, Juliette ^{[17
]}

Dunham, Chris ^{[17
]}

Scheinemann, Katrin ^{[18
]}

Michaud, Jean ^{[19
]}

Zelcer, Shayna ^{[20
]}

Ramsay, David ^{[20
]}

Cain, Jason ^{[21
]}

Brennan, Cameron ^{[22
,23
]}

Souweidane, Mark M. ^{[22
,23
]}

Jones, Chris ^{[9
]}

Allis, C. David ^{[7
]}

Brudno, Michael ^{[6
,24
]}

机构：

[1] Univ Toronto, Hosp Sick Children, Div Pathol, Toronto, ON M5G 1X8, Canada

[2] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada

[3] Univ Toronto, Fac Med, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[4] Duke Univ, Med Ctr, Div Pediat Hematol Oncol, Durham, NC USA

[5] McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[6] Univ Toronto, Dept Comp Sci, Toronto, ON, Canada

[7] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10021 USA

[8] Hosp Sick Children, Div Haematol Oncol, Toronto, ON, Canada

[9] Inst Canc Res, Div Canc Therapeut, London SW3 6JB, England

[10] Childrens Hosp & Clin Minnesota, Dept Pediat Hematol Oncol, Minneapolis, MN USA

[11] Childrens Natl Med Ctr, Ctr Genet Med, Washington, DC 20010 USA

[12] Ann & Robert H Lurie Childrens Hosp Chicago, Dept Pediat Hematol, Chicago, IL USA

[13] NYU, Langone Med Ctr, Inst Canc, Div Pediat Hematol Oncol & Neuropathol, New York, NY USA

[14] Childrens Hosp Colorado, Dept Pediat, Denver, CO USA

[15] Arnold Palmer Hosp Children, Dept Pathol, Orlando, FL USA

[16] Univ Calgary, Fac Med, Clark H Smith Brain Tumour Ctr, Calgary, AB, Canada

[17] BC Childrens Hosp, Dept Pediat Neurol & Neurooncol, Vancouver, BC, Canada

[18] McMaster Childrens Hosp, Div Hematol Oncol, Hamilton, ON, Canada

[19] Childrens Hosp Eastern Ontario, Dept Pathol & Lab Med, Ottawa, ON K1H 8L1, Canada

[20] Childrens Hosp London, Hlth Sci Ctr, Dept Hematol Oncol, London, ON, Canada

[21] Monash Inst Med Res, Monash Med Ctr, Clayton, Vic, Australia

[22] Weill Cornell Med Coll, Dept Neurol Surg, New York, NY USA

[23] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA

[24] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada

来源：

NATURE GENETICS | 2014年 / 46卷 / 05期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

FIBRODYSPLASIA OSSIFICANS PROGRESSIVA; BONE MORPHOGENETIC PROTEIN; BRAIN-STEM GLIOMAS; CELL-PROLIFERATION; ID2; EXPRESSION; HISTONE H3.3; CANCER; GENES; DIFFERENTIATION; FEATURES;

D O I：

10.1038/ng.2936

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

引用

页码：451 / 456

页数：6

共 24 条

[1]

Aurora Kinase B Is a Potential Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma [J].