Spatial heterogeneity in medulloblastoma.
Nat Genet. 2017 Apr 10;:
Authors: Morrissy AS, Cavalli FM, Remke M, Ramaswamy V, Shih DJ, Holgado BL, Farooq H, Donovan LK, Garzia L, Agnihotri S, Kiehna EN, Mercier E, Mayoh C, Papillon-Cavanagh S, Nikbakht H, Gayden T, Torchia J, Picard D, Merino DM, Vladoiu M, Luu B, Wu X, Daniels C, Horswell S, Thompson YY, Hovestadt V, Northcott PA, Jones DT, Peacock J, Wang X, Mack SC, Reimand J, Albrecht S, Fontebasso AM, Thiessen N, Li Y, Schein JE, Lee D, Carlsen R, Mayo M, Tse K, Tam A, Dhalla N, Ally A, Chuah E, Cheng Y, Plettner P, Li HI, Corbett RD, Wong T, Long W, Loukides J, Buczkowicz P, Hawkins CE, Tabori U, Rood BR, Myseros JS, Packer RJ, Korshunov A, Lichter P, Kool M, Pfister SM, Schüller U, Dirks P, Huang A, Bouffet E, Rutka JT, Bader GD, Swanton C, Ma Y, Moore RA, Mungall AJ, Majewski J, Jones SJ, Das S, Malkin D, Jabado N, Marra MA, Taylor MD
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.
PMID: 28394352 [PubMed - as supplied by publisher]