Morrissy A Sorana, Cavalli Florence M G, Remke Marc, Ramaswamy Vijay, Shih David J H, Holgado Borja L, Farooq Hamza, Donovan Laura K, Garzia Livia, Agnihotri Sameer, Kiehna Erin N, Mercier Eloi, Mayoh Chelsea, Papillon-Cavanagh Simon, Nikbakht Hamid, Gayden Tenzin, Torchia Jonathon, Picard Daniel, Merino Diana M, Vladoiu Maria, Luu Betty, Wu Xiaochong, Daniels Craig, Horswell Stuart, Thompson Yuan Yao, Hovestadt Volker, Northcott Paul A, Jones David T W, Peacock John, Wang Xin, Mack Stephen C, Reimand Jüri, Albrecht Steffen, Fontebasso Adam M, Thiessen Nina, Li Yisu, Schein Jacqueline E, Lee Darlene, Carlsen Rebecca, Mayo Michael, Tse Kane, Tam Angela, Dhalla Noreen, Ally Adrian, Chuah Eric, Cheng Young, Plettner Patrick, Li Haiyan I, Corbett Richard D, Wong Tina, Long William, Loukides James, Buczkowicz Pawel, Hawkins Cynthia E, Tabori Uri, Rood Brian R, Myseros John S, Packer Roger J, Korshunov Andrey, Lichter Peter, Kool Marcel, Pfister Stefan M, Schüller Ulrich, Dirks Peter, Huang Annie, Bouffet Eric, Rutka James T, Bader Gary D, Swanton Charles, Ma Yusanne, Moore Richard A, Mungall Andrew J, Majewski Jacek, Jones Steven J M, Das Sunit, Malkin David, Jabado Nada, Marra Marco A, Taylor Michael D
Developmental &Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nat Genet. 2017 May;49(5):780-788. doi: 10.1038/ng.3838. Epub 2017 Apr 10.
Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
单个肿瘤的物理隔离活检样本之间转录和遗传标记的空间异质性，对生物标志物的识别以及开发能有效对抗整个肿瘤的靶向治疗构成了重大障碍。我们结合转录组学和基因组图谱分析了35例患者多区域活检样本的空间异质性。髓母细胞瘤（MBs）而非高级别胶质瘤（HGGs）表现出空间均匀的转录组，这使得能够从单个活检样本中对肿瘤进行准确的亚组分类。相反，影响适合靶向治疗的基因的体细胞突变在MB、恶性胶质瘤和肾细胞癌（RCC）中表现出高度的空间异质性。在单个MB活检样本中发现的可操作靶点很少在整个肿瘤中呈克隆性，这使得针对单一靶点的单药治疗的疗效受到质疑。MB靶向治疗的临床试验应首先确保靶点突变在空间上的普遍存在性。
