nihms861288.pdf (2 MB)
Spatial heterogeneity in medulloblastoma
journal contributionposted on 2020-10-15, 08:49 authored by A Sorana Morrissy, Florence MG Cavalli, Marc Remke, Vijay Ramaswamy, David JH Shih, Borja L Holgado, Hamza Farooq, Laura K Donovan, Livia Garzia, Sameer Agnihotri, Erin N Kiehna, Eloi Mercier, Chelsea Mayoh, Simon Papillon-Cavanagh, Hamid Nikbakht, Tenzin Gayden, Jonathon Torchia, Daniel Picard, Diana M Merino, Maria Vladoiu, Betty Luu, Xiaochong Wu, Craig Daniels, Stuart Horswell, Yuan Yao Thompson, Volker Hovestadt, Paul A Northcott, David TW Jones, John Peacock, Xin Wang, Stephen C Mack, Jüri Reimand, Steffen Albrecht, Adam M Fontebasso, Nina Thiessen, Yisu Li, Jacqueline E Schein, Darlene Lee, Rebecca Carlsen, Michael Mayo, Kane Tse, Angela Tam, Noreen Dhalla, Adrian Ally, Eric Chuah, Young Cheng, Patrick Plettner, Haiyan I Li, Richard D Corbett, Tina Wong, William Long, James Loukides, Pawel Buczkowicz, Cynthia E Hawkins, Uri Tabori, Brian R Rood, John S Myseros, Roger J Packer, Andrey Korshunov, Peter Lichter, Marcel Kool, Stefan M Pfister, Ulrich Schüller, Peter Dirks, Annie Huang, Eric Bouffet, James T Rutka, Gary D Bader, Charles Swanton, Yusanne Ma, Richard A Moore, Andrew J Mungall, Jacek Majewski, Steven JM Jones, Sunit Das, David Malkin, Nada Jabado, Marco A Marra, Michael D Taylor
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.
AdultAgedAged, 80 and overCerebellar NeoplasmsChildChild, PreschoolCluster AnalysisDNA Copy Number VariationsFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticGenetic HeterogeneityGenome-Wide Association StudyHumansINDEL MutationMaleMedulloblastomaMiddle AgedMutationPolymorphism, Single NucleotidePrincipal Component AnalysisReverse Transcriptase Polymerase Chain ReactionTranscriptomeSwantonDevelopmental Biology11 Medical and Health Sciences06 Biological Sciences