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Subgroup-specific structural variation across 1,000 medulloblastoma genomes
Authors:Northcott Paul A  Shih David J H  Peacock John  Garzia Livia  Morrissy A Sorana  Zichner Thomas  Stütz Adrian M  Korshunov Andrey  Reimand Jüri  Schumacher Steven E  Beroukhim Rameen  Ellison David W  Marshall Christian R  Lionel Anath C  Mack Stephen  Dubuc Adrian  Yao Yuan  Ramaswamy Vijay  Luu Betty  Rolider Adi  Cavalli Florence M G  Wang Xin  Remke Marc  Wu Xiaochong  Chiu Readman Y B  Chu Andy  Chuah Eric  Corbett Richard D  Hoad Gemma R  Jackman Shaun D  Li Yisu  Lo Allan  Mungall Karen L  Nip Ka Ming  Qian Jenny Q  Raymond Anthony G J  Thiessen Nina T  Varhol Richard J  Birol Inanc  Moore Richard A  Mungall Andrew J
Affiliation:Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada.
Abstract:Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
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