The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
NATURE COMMUNICATIONS
Authors: Huether, Robert; Dong, Li; Chen, Xiang; Wu, Gang; Parker, Matthew; Wei, Lei; Ma, Jing; Edmonson, Michael N.; Hedlund, Erin K.; Rusch, Michael C.; Shurtleff, Sheila A.; Mulder, Heather L.; Boggs, Kristy; Vadordaria, Bhavin; Cheng, Jinjun; Yergeau, Donald; Song, Guangchun; Becksfort, Jared; Lemmon, Gordon; Weber, Catherine; Cai, Zhongling; Dang, Jinjun; Walsh, Michael; Gedman, Amanda L.; Faber, Zachary; Easton, John; Gruber, Tanja; Kriwacki, Richard W.; Partridge, Janet F.; Ding, Li; Wilson, Richard K.; Mardis, Elaine R.; Mullighan, Charles G.; Gilbertson, Richard J.; Baker, Suzanne J.; Zambetti, Gerard; Ellison, David W.; Zhang, Jinghui; Downing, James R.
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.
Landscape of somatic mutations and clonal evolution in mantle cell lymphoma
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Authors: Bea, Silvia; Valdes-Mas, Rafael; Navarro, Alba; Salaverria, Itziar; Martin-Garcia, David; Jares, Pedro; Gine, Eva; Pinyol, Magda; Royo, Cristina; Nadeu, Ferran; Conde, Laura; Juan, Manel; Clot, Guillem; Vizan, Pedro; Di Croce, Luciano; Puente, Diana A.; Lopez-Guerra, Monica; Moros, Alexandra; Roue, Gael; Aymerich, Marta; Villamor, Neus; Colomo, Lluis; Martinez, Antonio; Valera, Alexandra; Martin-Subero, Jose I.; Amador, Virginia; Hernandez, Luis; Rozman, Maria; Enjuanes, Anna; Forcada, Pilar; Muntanola, Ana; Hartmann, Elena M.; Calasanz, Maria J.; Rosenwald, Andreas; Ott, German; Hernandez-Rivas, Jesus M.; Klapper, Wolfram; Siebert, Reiner; Wiestner, Adrian; Wilson, Wyndham H.; Colomer, Dolors; Lopez-Guillermo, Armando; Lopez-Otin, Carlos; Puente, Xose S.; Campo, Elias
Abstract
Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.
COA
Publication 
Loading ......
