The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes - PubMed (original) (raw)

Li Dong 2, Xiang Chen 3, Gang Wu 3, Matthew Parker 3, Lei Wei 3, Jing Ma 4, Michael N Edmonson 3, Erin K Hedlund 3, Michael C Rusch 3, Sheila A Shurtleff 4, Heather L Mulder 5, Kristy Boggs 5, Bhavin Vadordaria 5, Jinjun Cheng 4, Donald Yergeau 5, Guangchun Song 4, Jared Becksfort 3, Gordon Lemmon 3, Catherine Weber 4, Zhongling Cai 4, Jinjun Dang 4, Michael Walsh 6, Amanda L Gedman 4, Zachary Faber 4, John Easton 5, Tanja Gruber 7, Richard W Kriwacki 8, Janet F Partridge 9, Li Ding 10, Richard K Wilson 10, Elaine R Mardis 10, Charles G Mullighan 4, Richard J Gilbertson 11, Suzanne J Baker 11, Gerard Zambetti 9, David W Ellison 4, Jinghui Zhang 3, James R Downing 4

Affiliations

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

Robert Huether et al. Nat Commun. 2014.

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.

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Conflict of interest statement

Competing Financial interests

The authors declare no competing financial interests.

Figures

Figure 1

Figure 1. The landscape of somatic mutations in epigenetic regulators in 21 pediatric cancer subtypes

(a) Eight classes of epigenetic genes were interrogated across the cohort (Histone Writer, Bind Histone Writer, Histone Eraser, Bind Histone Eraser, Histone, Histone Reader, Chromatin Modifier, and DNA modifier), with the numbers of genes within each class indicated. (b) Fraction of tumors in each cancer subtype with at least one mutation in each class of epigenetic genes. Only sequence mutations (i.e. SNVs and indels) with a mutant allele fraction >0.3 (i.e. present in the dominant clone) were included in the analysis (c) Top 15 most frequently mutated genes colored coded by class.

Figure 2

Figure 2. Epigenetic complexes affected by recurrently mutated proteins in pediatric cancer

A subset (35%) of the recurrently mutated epigenetic regulatory proteins (green circles) function within one or more of eight key epigenetic protein complexes (red nodes). Individual somatic mutation were also detected in additional components of these complexes (blue circles), whereas other components were never found to be mutated within our patient cohort (white circles). The size of each green circle is proportional to the number of mutated samples. The distance between the circles and the central complex node indicates whether the protein is a core (short) or transient (long) component of the complex. Recurrently mutated proteins that do not belong to one of these core complexes are presented on the right as unattached circles. The color of each protein name conforms to the color scheme for epigenetic regulatory classes presented in Figure 1.

Figure 3

Figure 3. Novel ALL-specific mutations of USP7

(a) Location of the identified USP7 somatic mutations relative to the TRAF (tumor necrosis factor [TNF] receptor-associated factor), catalytic, and HUBL1-5 (USP7/HAUSP ubiquitin-like domain) domains (colored red, green, black, orange, teal, purple and blue respectively). Mutations C300R, D483fs, and Q821R occurred at mutant allele frequencies (MAF) below 30%, whereas all other mutations occurred with MAF >30% and thus represent the dominant malignant clone. (b) Location of the missense somatic mutations (C300R, D305G, and A381T: magenta space filled) within the USP7 catalytic domain (green cartoon) – Ubiquitin (peach cartoon) interface. Specific residues and interactions between USP7 and Ubiquitin are shown as sticks and black dots and further described in Supplementary Fig. 3–5. (c and d) 293T cells were transfected with USP7 WT or mutant constructs as indicated. Protein extracts were prepared at 72 hours post transfection and subjected to western blot analysis using antibodies to the indicated proteins. Bars represent mean of protein band intensities of 3 replicates ± S.E.M. (e and f). The level of Histone H2B ubiquityl Lys120 (H2BK120ub1) and total H2B were detected at 72 hours by immunoblot using an antibody specific for mono-ubiquitinated and total H2B. Bars represent mean of protein band intensities of 3 replicates ± S.E.M. NT, untransfected control. The statistical significance of the changes observed between wild type and USP7 mutants were assessed by t-test with * equal to a p<0.05 and ** equal to p<0.01.

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