title: Clinical implications ofDNMT3Amutations in a Southeast Asian cohort of acute myeloid leukaemia patients.
abstract: OBJECTIVE
  In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML).DNMT3Ais a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance ofDNMT3Amutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications ofDNMT3Amutations in a Southeast Asian cohort of AML patients.
  
  
  METHODS
  DNMT3Amutations were identified using a targeted next-generation sequencing panel in 157 AML patients. We studied the molecular and clinical features of patients withDNMT3Amutations and assessed the prognostic impact ofDNMT3Amutations.
  
  
  RESULTS
  DNMT3Amutations were found in 33 of 157 (21.0%) AML patients. 114 patients were included for statistical analysis. Pretreatment data revealed that patients withDNMT3Amutations were older (≥60 years old), had a higher white blood cell count at diagnosis, had more adverse cytogenetic risk profiles and were more often associated withNPM1mutations compared with patients with wild-typeDNMT3A. Survival analysis showed that DNMT3A mutations were associated with poorer clinical outcomes. This was especially when associated with NPM1 and FLT3-ITD mutations (AMLNPM1/FLT3/DNMT3A), which are common. The AMLNPM1/FLT3/DNMT3Asubtype was an independent predictor for poorer overall survival (OS). Other independent risk factors for poorer OS include advanced age at diagnosis and adverse cytogenetic risk stratification.
  
  
  CONCLUSIONS
  DNMT3Amutations are associated with an unfavourable clinical outcome in our Southeast Asian AML patient cohort. In particular, AMLNPM1/FLT3/DNMT3Apatients had the poorest prognosis.
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: Marcus
authors.initials: M
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: Isaac K S
authors.initials: IKS
authors.lastname: Ng
authors.affiliation: Investigational Medicine Unit, National University Health System, Singapore, Singapore.
authors.forename: Zhaojin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore, Singapore.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ban
authors.affiliation: Department of Laboratory Medicine, Molecular Diagnosis Centre, National University Health System, Singapore, Singapore.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ng
authors.affiliation: Department of Laboratory Medicine, Molecular Diagnosis Centre, National University Health System, Singapore, Singapore.
authors.forename: Lily
authors.initials: L
authors.lastname: Chiu
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.
authors.forename: Elaine
authors.initials: E
authors.lastname: Seah
authors.affiliation: Department of Laboratory Medicine, Molecular Diagnosis Centre, National University Health System, Singapore, Singapore.
authors.forename: Mingxuan
authors.initials: M
authors.lastname: Lin
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
authors.forename: Bee Choo
authors.initials: BC
authors.lastname: Tai
authors.affiliation: Department of Laboratory Medicine, Molecular Diagnosis Centre, National University Health System, Singapore, Singapore.
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.
authors.forename: Chin Hin
authors.initials: CH
authors.lastname: Ng
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore.|Cancer Science Institute Singapore, National University of Singapore, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000328:Adult; D000368:Aged; D001210:Asia, Southeastern / Q000453:epidemiology / Q000208:ethnology; D002681:China / Q000453:epidemiology / Q000208:ethnology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007194:India / Q000453:epidemiology / Q000208:ethnology; D015470:Leukemia, Myeloid, Acute / Q000208:ethnology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: CANCER RESEARCH; HAEM-ONCOLOGY; diagnostic screening