Nat Commun. 2014 Apr 8;5:3630. doi: 10.1038/ncomms4630.
The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.
Huether R1, Dong L2, Chen X3, Wu G3, Parker M3, Wei L3, Ma J4, Edmonson MN3, Hedlund EK3, Rusch MC3, Shurtleff SA4, Mulder HL5, Boggs K5, Vadordaria B5, Cheng J4, Yergeau D5, Song G4, Becksfort J3, Lemmon G3, Weber C4, Cai Z4, Dang J4, Walsh M6, Gedman AL4, Faber Z4, Easton J5, Gruber T7, Kriwacki RW8, Partridge JF9, Ding L10, Wilson RK10, Mardis ER10, Mullighan CG4, Gilbertson RJ11, Baker SJ11, Zambetti G9, Ellison DW4, Zhang J3, Downing JR4.
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.
- [PubMed - in process]