Nikbakht Hamid, Panditharatna Eshini, Mikael Leonie G, Li Rui, Gayden Tenzin, Osmond Matthew, Ho Cheng-Ying, Kambhampati Madhuri, Hwang Eugene I, Faury Damien, Siu Alan, Papillon-Cavanagh Simon, Bechet Denise, Ligon Keith L, Ellezam Benjamin, Ingram Wendy J, Stinson Caedyn, Moore Andrew S, Warren Katherine E, Karamchandani Jason, Packer Roger J, Jabado Nada, Majewski Jacek, Nazarian Javad
Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A 1B1.
McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada H3A 0G1.
Nat Commun. 2016 Apr 6;7:11185. doi: 10.1038/ncomms11185.
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.
弥漫性脑桥内在型胶质瘤（DIPG）是致命的儿童脑肿瘤，针吸活检有助于指导诊断和靶向治疗。为了解决空间异质性问题，我们分析了9例DIPG患者全脑尸检不同神经解剖结构的134个标本。进化重建表明，组蛋白3（H3）K27M（包括H3.2K27M）突变可能首先出现，并且在整个肿瘤及其扩散过程中，从诊断到终末期疾病，始终与特定的、高保真的必需伴侣相关，提示肿瘤发生存在相互需求。这些与H3K27M普遍相关的突变涉及TP53细胞周期（TP53/PPM1D）或特定生长因子途径（ACVR1/PIK3R1）的改变。后期致癌改变出现在亚克隆中，且常影响PI3K途径。我们的研究结果与肿瘤早期扩散至脑干以外包括大脑一致。DIPG主要驱动突变的时空同质性意味着它们将被有限的活检所捕获，并强调需要开发专门针对必需癌组蛋白伙伴关系的治疗方法。
