Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

被引：195

作者：

Nikbakht, Hamid ^{[1
,2
,3
]}

Panditharatna, Eshini ^{[4
,5
]}

Mikael, Leonie G. ^{[6
,7
]}

Li, Rui ^{[1
,2
,3
]}

Gayden, Tenzin ^{[1
]}

Osmond, Matthew ^{[1
,2
,3
]}

Ho, Cheng-Ying ^{[8
]}

Kambhampati, Madhuri ^{[4
]}

Hwang, Eugene I. ^{[9
]}

Faury, Damien ^{[6
,7
]}

Siu, Alan ^{[10
]}

Papillon-Cavanagh, Simon ^{[1
,2
,3
]}

Bechet, Denise ^{[1
]}

Ligon, Keith L. ^{[11
]}

Ellezam, Benjamin ^{[12
]}

Ingram, Wendy J. ^{[13
]}

Stinson, Caedyn ^{[14
]}

Moore, Andrew S. ^{[13
,14
,15
]}

Warren, Katherine E. ^{[16
]}

Karamchandani, Jason ^{[17
]}

Packer, Roger J. ^{[18
]}

Jabado, Nada ^{[1
,6
,7
]}

Majewski, Jacek ^{[1
,2
,3
]}

Nazarian, Javad ^{[4
,19
]}

机构：

[1] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[2] McGill Univ, Montreal, PQ H3A 0G1, Canada

[3] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada

[4] Childrens Natl Hlth Syst, Med Genet Res Ctr, Washington, DC 20010 USA

[5] George Washington Univ, Sch Med & Hlth Sci, Inst Biomed Sci, Washington, DC 20052 USA

[6] McGill Univ, Dept Pediat, Montreal, PQ H4A 3J1, Canada

[7] McGill Univ, Heath Ctr, Res Inst, Montreal, PQ H4A 3J1, Canada

[8] Childrens Natl Hlth Syst, Div Pathol, Washington, DC 20010 USA

[9] Childrens Natl Hlth Syst, Ctr Canc & Blood Disorders, Washington, DC 20010 USA

[10] George Washington Univ, Sch Med & Hlth Sci, Dept Neurol Surg, Washington, DC 20052 USA

[11] Dana Farber Canc Inst, Dept Med Oncol, Ctr Mol Oncol Pathol, Boston, MA 02115 USA

[12] Univ Montreal, Dept Pathol, CHU Ste Justine, Montreal, PQ H3T 1C5, Canada

[13] Univ Queensland, Child Hlth Res Ctr, Brisbane, Qld 4101, Australia

[14] Univ Queensland, Diamantina Inst, Brisbane, Qld 4102, Australia

[15] Childrens Hlth Queensland Hosp & Hlth Serv, Oncol Serv, Brisbane, Qld 4101, Australia

[16] NCI, NIH, Bethesda, MD 20892 USA

[17] McGill Univ, Dept Pathol, Montreal Neurol Hosp, Montreal, PQ H3A 2B4, Canada

[18] Childrens Natl Hlth Syst, Ctr Neurosci & Behav Med, Brain Tumour Inst, Washington, DC 20010 USA

[19] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20052 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

INTRATUMOR HETEROGENEITY; HISTONE H3.3; GRADE; SUBGROUPS; EVOLUTION; ACVR1; REVEALS; PATHWAY;

D O I：

10.1038/ncomms11185

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M-including H3.2K27M-mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.

引用

页数：8

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