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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.


ABSTRACT: Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-grade gliomas, T-lineage acute lymphoblastic leukaemia and medulloblastoma, and a paucity of mutations in low-grade glioma and retinoblastoma. The most frequently mutated genes are H3F3A, PHF6, ATRX, KDM6A, SMARCA4, ASXL2, CREBBP, EZH2, MLL2, USP7, ASXL1, NSD2, SETD2, SMC1A and ZMYM3. We identify novel loss-of-function mutations in the ubiquitin-specific processing protease 7 (USP7) in paediatric leukaemia, which result in decreased deubiquitination activity. Collectively, our results help to define the landscape of mutations in epigenetic regulatory genes in paediatric cancer and yield a valuable new database for investigating the role of epigenetic dysregulations in cancer.

SUBMITTER: Huether R 

PROVIDER: S-EPMC4119022 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.

Huether Robert R   Dong Li L   Chen Xiang X   Wu Gang G   Parker Matthew M   Wei Lei L   Ma Jing J   Edmonson Michael N MN   Hedlund Erin K EK   Rusch Michael C MC   Shurtleff Sheila A SA   Mulder Heather L HL   Boggs Kristy K   Vadordaria Bhavin B   Cheng Jinjun J   Yergeau Donald D   Song Guangchun G   Becksfort Jared J   Lemmon Gordon G   Weber Catherine C   Cai Zhongling Z   Dang Jinjun J   Walsh Michael M   Gedman Amanda L AL   Faber Zachary Z   Easton John J   Gruber Tanja T   Kriwacki Richard W RW   Partridge Janet F JF   Ding Li L   Wilson Richard K RK   Mardis Elaine R ER   Mullighan Charles G CG   Gilbertson Richard J RJ   Baker Suzanne J SJ   Zambetti Gerard G   Ellison David W DW   Zhang Jinghui J   Downing James R JR  

Nature communications 20140408


Studies of paediatric cancers have shown a high frequency of mutation across epigenetic regulators. Here we sequence 633 genes, encoding the majority of known epigenetic regulatory proteins, in over 1,000 paediatric tumours to define the landscape of somatic mutations in epigenetic regulators in paediatric cancer. Our results demonstrate a marked variation in the frequency of gene mutations across 21 different paediatric cancer subtypes, with the highest frequency of mutations detected in high-g  ...[more]

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