Spatial heterogeneity in medulloblastoma

• Published in: Nature genetics Vol. 49; no. 5; pp. 780 - 788
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2017; Nature Publishing Group
• Subjects: 45/23; 45/61; 631/208/212/2019; 631/208/212/2166; 631/67/1922; 692/308/575; Adult; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Biology; Biomarkers; Biomedicine; Biopsy; Brain cancer; Cancer Research; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - pathology; Child; Child, Preschool; Children & youth; Cluster Analysis; Colleges & universities; Consortia; DNA Copy Number Variations; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Gene Function; Genetic Heterogeneity; Genetic markers; Genetics; Genome-Wide Association Study; Genomes; Glioma; Hematology; Heterogeneity; Hospitals; Human Genetics; Humans; Immunology; INDEL Mutation; Kidney cancer; Laboratories; letter; Male; Medical research; Medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - pathology; Middle Aged; Mutation; Neuropathology; Neurosurgery; Oncology; Pediatrics; Polymorphism, Single Nucleotide; Principal Component Analysis; Renal cell carcinoma; Research centers; Reverse Transcriptase Polymerase Chain Reaction; Transcriptome; Tumors; Germany
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3838

Michael Taylor, Marco Marra and colleagues analyze spatial tumor heterogeneity in 9 medulloblastomas, 16 high-grade gliomas and 10 renal cell carcinomas, using a combination of transcriptomic and genomic profiling of multiregional biopsies. They find that medulloblastomas have spatially homogeneous transcriptomes, whereas somatic mutations that affect genes suitable for targeted therapeutics are spatially heterogeneous.
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.