The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes.
نویسندگان
چکیده
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.
منابع مشابه
Mutations in epigenetic regulators including SETD2 are gained during relapse in pediatric acute lymphoblastic leukemia
Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis-remission-relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2,...
متن کاملTitle: Chromatin marks govern mutation landscape of cancer at early stage
7 * Co-corresponding authors 8 9 10 Accumulation of somatic mutations over time leads to tissue abnormalities, such as cancer. 11 Somatic mutation rates vary across the genome in a cell-type specific manner, depending on 12 the types of mutation processes 1-7. Although recent studies have identified several 13 determinants relevant to the establishment of the cancer mutation landscape 8-13 , th...
متن کاملOncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples
The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate...
متن کاملA Review of Driver Genetic Alterations in Thyroid Cancers
Thyroid cancer is a frequent endocrine related malignancy with continuous increasing incidence. There has been moving development in understanding its molecular pathogenesis recently mainly through the explanation of the original role of several key signaling pathways and related molecular distributors. Central to these mechanisms are the genetic and epigenetic alterations in these pathways, su...
متن کاملThe Relative Contributions of Germline Variation, Epimutation, and Somatic Mutation to Paediatric Leukaemia Predisposition
The next-generation sequencing era has repeatedly demonstrated that the amount of acquired somatic mutations in paediatric cancers can rarely account for the total incidence of any cancer subtype. In addition, many cancer-related mutations can be found in healthy individuals. These findings strongly suggest that additional genetic or epigenetic variation is required for malignant transformation...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Nature communications
دوره 5 شماره
صفحات -
تاریخ انتشار 2014