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Exome sequencing identifiessomatic mutations of DNA methyltransferase gene DNMT3A

?2011 N a t u r e A m e r i c a , I n c . A l l r i g h t s r e s e r v e d .Nature GeNetics ?ADVANCE ONLINE PUBLICATION

Exome sequencing identifiessomatic mutations of DNA methyltransferase gene DNMT3A

A r t i c l e s

Individuals with acute monocytic leukemia, or AML-M5, have a poor prognosis associated with hyperleukocytosis and extramedul-lary involvement 1–5. The 3-year disease-free survival rate for indivi-duals with AML-M5 is ~25% (ref. 6). Two morphological entities of AML-M5 are recognized: the bone marrow and peripheral blood may be overwhelmed either by monoblasts (in acute monoblastic leukemia) or by more differentiated promonocytes and monocytes (in acute promonocytic or monocytic leukemia)1. Chromosomal translocations involving MLL on 11q23 are mostly found in AML-M5 (ref. 7). Mutations in NPM1, FLT3 and NRAS have also been reported in this disease 8–10. However, these genetic changes occur only in a subset of AML-M5 leukemia cases.The development of massively parallel sequencing technologies makes it feasible to catalog all classes of somatically acquired mutations in a cancer 11–13. However, a major challenge of cancer genome analysis is to identify ‘driver’ mutations 12, and several recent genome studies of leukemias and solid tumors have con-centrated analysis on coding regions (exomes) to increase the likeli-hood of identifying driver mutations 14,15. To gain new insight into leukemogenesis and the molecular basis underlying the clinical heterogeneity of AML-M5, we carried out exome sequencing and subsequent Sanger sequencing analysis in a large series of indivi-duals with this disease.RESULTS Discovery?of?somatic?mutations?through?exome?sequencing We captured and sequenced the exomes from nine paired samples of AML-M5 cases (initial sequencing set; Supplementary Table 1) with bone marrow samples obtained at the time of diagnosis and c ontrol peripheral blood specimens obtained after complete remis-sion. The captured target in each exome was 24 Mb. The average coverage of each base in the targeted regions was 100-fold, and 95.3% of these bases were covered sufficiently deeply for variant calling (≥10× coverage) (Supplementary Table 2). We used an in-house software system to identify somatic mutations by com-paring variants identified in bone marrow exome data set against dbSNP and germline variants present in peripheral blood control samples (see Online Methods). We identified 266 potential somatic sequence changes including 220 single-nucleotide variations (SNVs) and 46 small insertions or deletions (indels; Supplementary Table 3 and Supplementary Fig. 1).We focused our analysis on changes predicted to affect protein-coding sequence, including 59 non-synonymous substitutions and 10 indels affecting integrity of the open reading frame (ORF) (Supplementary Table 3). For validation, we amplified the corres-ponding genomic region directly from original samples using a PCR assay and carried out Sanger sequencing. Of the non-synonymous

Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia

Xiao-Jing Yan 1,2,4, Jie Xu 1,4, Zhao-Hui Gu 3,4, Chun-Ming Pan 1,4, Gang Lu 1,4, Yang Shen 1, Jing-Yi Shi 1, Yong-Mei Zhu 1, Lin Tang 1, Xiao-Wei Zhang 1, Wen-Xue Liang 1, Jian-Qing Mi 1, Huai-Dong Song 1, Ke-Qin Li 1, Zhu Chen 1,3 & Sai-Juan Chen 1,3Abnormal?epigenetic?regulation?has?been?implicated?in?oncogenesis.?We?report?here?the?identification?of?somatic?mutations?by?exome?sequencing?in?acute?monocytic?leukemia,?the?M5?subtype?of?acute?myeloid?leukemia?(AML-M5).?We?discovered?mutations?in?DNMT3A ?(encoding?DNA?methyltransferase?3A)?in?23?of? 2?(20.5%)?cases.?The?DNMT3A?mutants?showed?reduced?enzymatic?activity?or?aberrant?affinity?to?histone?H3?in vitro .?Notably,?there?were?alterations?of?DNA?methylation?patterns?and/or?gene?expression?profiles?(such?as?HOXB ?genes)?in?samples?with?DNMT3A ?mutations?as?compared?with?those?without?such?changes.?Leukemias?with?DNMT3A ?mutations?constituted?a?group?of?poor?prognosis?with?elderly?disease?onset?and?of?promonocytic?as?well?as?monocytic?predominance?among?AML-M5?individuals.?Screening?other?leukemia?subtypes?showed?Arg882?alterations?in? 3.6%?of?acute?myelomonocytic?leukemia?(AML-M4)?cases.?Our?work?suggests?a?contribution?of?aberrant?DNA?methyltransferase?activity?to?the?pathogenesis?of?acute?monocytic?leukemia?and?provides?a?useful?new?biomarker?for?relevant?cases.1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2Department of Hematology, The First Hospital of China Medical Univ
ersity, Shenyang, China. 3Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China. 4These authors contributed equally to this work. Correspondence should be addressed to Z.C. ([email protected]://www.ffiun.com/doc/67085e126c175f0e7cd1378c.html ) or S.-J.C. ([email protected]://www.ffiun.com/doc/67085e126c175f0e7cd1378c.html ).

Xiao-Jing Yan 1,2,4, Jie Xu 1,4, Zhao-Hui Gu 3,4, Chun-Ming Pan 1,4, Gang Lu 1,4, Yang Shen 1, Jing-Yi Shi 1, Yong-Mei Zhu 1, Lin Tang 1, Xiao-Wei Zhang 1, Wen-Xue Liang 1, Jian-Qing Mi 1, Huai-Dong Song 1, Ke-Qin Li 1, Zhu Chen 1,3 & Sai-Juan Chen 1,3Abnormal?epigenetic?regulation?has?been?implicated?in?oncogenesis.?We?report?here?the?identification?of?somatic?mutations?by?exome?sequencing?in?acute?monocytic?leukemia,?the?M5?subtype?of?acute?myeloid?leukemia?(AML-M5).?We?discovered?mutations?in?DNMT3A ?(encoding?DNA?methyltransferase?3A)?in?23?of? 2?(20.5%)?cases.?The?DNMT3A?mutants?showed?reduced?enzymatic?activity?or?aberrant?affinity?to?histone?H3?in vitro .?Notably,?there?were?alterations?of?DNA?methylation?patterns?and/or?gene?expression?profiles?(such?as?HOXB ?genes)?in?samples?with?DNMT3A ?mutations?as?compared?with?those?without?such?changes.?Leukemias?with?DNMT3A ?mutations?constituted?a?group?of?poor?prognosis?with?elderly?disease?onset?and?of?promonocytic?as?well?as?monocytic?predominance?among?AML-M5?individuals.?Screening?other?leukemia?subtypes?showed?Arg882?alterations?in? 3.6%?of?acute?myelomonocytic?leukemia?(AML-M4)?cases.?Our?work?suggests?a?contribution?of?aberrant?DNA?methyltransferase?activity?to?the?pathogenesis?of?acute?monocytic?leukemia?and?provides?a?useful?new?biomarker?for?relevant?cases.1State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 2Department of Hematology, The First Hospital of China Medical University, Shenyang, China. 3Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China. 4These authors contributed equally to this work. Correspondence should be addressed to Z.C. ([email protected]://www.ffiun.com/doc/67085e126c175f0e7cd1378c.html ) or S.-J.C. ([email protected]://www.ffiun.com/doc/67085e126c175f0e7cd1378c.html ).

Received 13 October 2010; accepted 15 February 2011; published online 13 March 2011; doi:10.1038/ng.788

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