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Clinical implications of DNMT3A mutations in a Southeast Asian cohort of acute myeloid leukaemia patients
  1. Marcus Tan1,
  2. Isaac K S Ng1,
  3. Zhaojin Chen2,
  4. Kenneth Ban1,
  5. Christopher Ng3,
  6. Lily Chiu3,
  7. Elaine Seah4,
  8. Mingxuan Lin3,
  9. Bee Choo Tai5,
  10. Benedict Yan3,
  11. Chin Hin Ng4,
  12. Wee-Joo Chng4,6,7
  1. 1Department of Biochemistry, National University of Singapore, Singapore, Singapore
  2. 2Investigational Medicine Unit, National University Health System, Singapore, Singapore
  3. 3Department of Laboratory Medicine, Molecular Diagnosis Centre, National University Health System, Singapore, Singapore
  4. 4Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore
  5. 5Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  6. 6Cancer Science Institute Singapore, National University of Singapore, Singapore, Singapore
  7. 7Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
  1. Correspondence to Professor Wee-Joo Chng, Cancer Science Institute Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore; mdccwj{at}nus.edu.sg or Dr Chin Hin Ng, Department of Haematology-Oncology, National University Cancer Institute, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore 119228, Singapore; chin_hin_ng{at}nuhs.edu.sg

Abstract

Aims In recent years, genomic technologies have enabled the identification of mutations in acute myeloid leukaemia (AML). DNMT3A is a recurrently mutated epigenetic modifier gene in AML. To date, the prognostic significance of DNMT3A mutations has not been studied in a Southeast Asian AML population. We sought to investigate the clinical implications of DNMT3A mutations in a Southeast Asian cohort of AML patients.

Methods DNMT3A mutations were identified using a targeted next-generation sequencing panel in 157 AML patients. We studied the molecular and clinical features of patients with DNMT3A mutations and assessed the prognostic impact of DNMT3A mutations.

Results DNMT3A mutations were found in 33 of 157 (21.0%) AML patients. 114 patients were included for statistical analysis. Pretreatment data revealed that patients with DNMT3A mutations 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 with NPM1 mutations compared with patients with wild-type DNMT3A. 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/DNMT3A subtype 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 DNMT3A mutations are associated with an unfavourable clinical outcome in our Southeast Asian AML patient cohort. In particular, AMLNPM1/FLT3/DNMT3A patients had the poorest prognosis.

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Footnotes

  • MT and IKSN are joint first author of this paper.

  • Handling editor Mary Frances McMullin

  • Contributors MT and IKSN contributed equally. MT, IKSN and BY wrote the manuscript. CN and LC performed the experiments. MT, IKSN, KB, ML, ZC, BCT, BY and CHN analysed the data. ES organised the clinical samples. BY, CHN and W-JC designed the study. Manuscript was critically reviewed by all the authors.

  • Funding This work was partly supported by Singapore Cancer Syndicate Grant. This research was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centers of Excellence initiative. W-JC is supported by NMRC Clinician Scientist Investigator award.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board, NUHS (reference number 2015/00111) and National Healthcare Group Domain Specific Review Board (NHG DSRB).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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