title: Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia.
abstract: OBJECTIVE
  To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia.
  
  
  METHODS
  Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation).
  
  
  RESULTS
  DNMT3A mutations (DNMT3A(MUT)) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3A(MUT) had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3A(MUT) was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3A(MUT) did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A.
  
  
  CONCLUSIONS
  These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation.
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom. rosemary.gale@ucl.ac.uk.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lamb
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Allen
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Dima
authors.initials: D
authors.lastname: El-Sharkawi
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Stowe
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jenkinson
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Tinsley
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Glenda
authors.initials: G
authors.lastname: Dickson
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Burnett
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hills
authors.affiliation: Rosemary E. Gale, Katarina Lamb, Christopher Allen, Dima El-Sharkawi, Cassandra Stowe, Sarah Jenkinson, Steven Tinsley, Glenda Dickson, and David C. Linch, University College London Cancer Institute, London; and Alan K. Burnett and Robert K. Hills, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D015331:Cohort Studies; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D000090243:Nucleophosmin; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A