Integrated genomic profiling, therapy response, and survival in adult acute myelogenous leukemia

Clin Cancer Res. 2015 May 1;21(9):2045-56. doi: 10.1158/1078-0432.CCR-14-0921. Epub 2015 Feb 4.


Purpose: Recurrent gene mutations, chromosomal translocations, and acquired genomic copy number aberrations (aCNA) have been variously associated with acute myelogenous leukemia (AML) patient outcome. However, knowledge of the co-occurrence of such lesions and the relative influence of different types of genomic alterations on clinical outcomes in AML is still evolving.

Experimental design: We performed SNP 6.0 array-based genomic profiling of aCNA/copy neutral loss-of-heterozygosity (cnLOH) along with sequence analysis of 13 commonly mutated genes on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML.

Results: TP53 and RUNX1 mutations are strongly associated with the presence of SNP-A-based aCNA/cnLOH, while FLT3 and NPM1 mutations are strongly associated with the absence of aCNA/cnLOH. The presence of mutations in RUNX1, ASXL1, and TP53, elevated SNP-A-based genomic complexity, and specific recurrent aCNAs predicted failure to achieve a complete response to induction chemotherapy. The presence of ≥1 aCNA/cnLOH and higher thresholds predicted for poor long-term survival irrespective of TP53 status, and the presence of ≥1 aCNA/cnLOH added negative prognostic information to knowledge of mutations in TET2, IDH1, NPM1, DNMT3A, and RUNX1. Results of multivariate analyses support a dominant role for TP53 mutations and a role for elevated genomic complexity as predictors of short survival in AML.

Conclusions: Integrated genomic profiling of a clinically relevant adult AML cohort identified genomic aberrations most associated with SNP-A-based genomic complexity, resistance to intensive induction therapies, and shortened overall survival. Identifying SNP-A-based lesions adds prognostic value to the status of several recurrently mutated genes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • DNA Mutational Analysis
  • Female
  • Gene Expression Profiling
  • Humans
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / mortality*
  • Leukemia, Myeloid, Acute / therapy*
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Nucleophosmin
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Proportional Hazards Models
  • Transcriptome