Mackay Alan, Burford Anna, Carvalho Diana, Izquierdo Elisa, Fazal-Salom Janat, Taylor Kathryn R, Bjerke Lynn, Clarke Matthew, Vinci Mara, Nandhabalan Meera, Temelso Sara, Popov Sergey, Molinari Valeria, Raman Pichai, Waanders Angela J, Han Harry J, Gupta Saumya, Marshall Lynley, Zacharoulis Stergios, Vaidya Sucheta, Mandeville Henry C, Bridges Leslie R, Martin Andrew J, Al-Sarraj Safa, Chandler Christopher, Ng Ho-Keung, Li Xingang, Mu Kun, Trabelsi Saoussen, Brahim Dorra H'mida-Ben, Kisljakov Alexei N, Konovalov Dmitry M, Moore Andrew S, Carcaboso Angel Montero, Sunol Mariona, de Torres Carmen, Cruz Ofelia, Mora Jaume, Shats Ludmila I, Stavale João N, Bidinotto Lucas T, Reis Rui M, Entz-Werle Natacha, Farrell Michael, Cryan Jane, Crimmins Darach, Caird John, Pears Jane, Monje Michelle, Debily Marie-Anne, Castel David, Grill Jacques, Hawkins Cynthia, Nikbakht Hamid, Jabado Nada, Baker Suzanne J, Pfister Stefan M, Jones David T W, Fouladi Maryam, von Bueren André O, Baudis Michael, Resnick Adam, Jones Chris
Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK; Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
Cancer Cell. 2017 Oct 9;32(4):520-537.e5. doi: 10.1016/j.ccell.2017.08.017. Epub 2017 Sep 28.
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
我们在对1000多例病例的综合分析中，整理了来自157例未发表的儿童高级别胶质瘤和弥漫性内生性脑桥胶质瘤病例的数据以及20个公开可用的数据集。我们在组蛋白突变亚组中鉴定出共分离突变，包括H3.3G34R/V中FBXW7缺失、H3.3K27M中TOP3A重排以及H3.1K27M中BCOR突变。组蛋白野生型亚组通过关键致癌事件的存在或更类似于低级别肿瘤的甲基化谱来细化。基因组畸变随年龄增加，突出了婴儿群体在生物学和临床上的独特性。在一小部分肿瘤中可见不常见的信号通路失调，进一步明确了该疾病的分子多样性，为生物学研究开辟了道路，并为功能明确的未来治疗分层提供了基础。
