Integrated Genomic Profiling, Therapy Response And Survival In Adult Acute Myelogenous Leukemia

Recurrent gene mutations, chromosomal translocations, acquired genomic copy number aberrations (aCNA) and copy-neutral loss-of-heterozygosity (cnLOH) underlie the genomic pathogenesis of acute myelogenous leukemia (AML). Genomic lesion types from all of these categories have been variously associated with AML patient outcome. However, the patterns of co-occurrence of such lesions are only now beginning to be defined, and we seek to further delineate the relative influence of different types of genomic alterations on clinical outcomes in AML. In this study, we performed SNP 6.0 array-based genomic profiling of aCNA/cnLOH along with sequence analysis of 13 recurrently 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. We identify positive and negative associations of gene mutations, specific aCNA/cnLOH or total aCNA/cnLOH counts with different AML types as well as the associations of specific mutations with overall genomic complexity or genomic stability. Further, we show that NPM1, RUNX1, ASXL1 and TP53 mutations, elevated SNP-A-based genomic complexity, and specific recurrent aCNAs predict response to induction chemotherapy. Finally, results of comprehensive multivariate analyses support a dominant role for TP53 mutations or elevated genomic complexity as predictors of short survival in AML. Integrated genomic profiling of a clinically relevant adult AML population reveals the interplay between gene mutations, recurrent aCNAs, and SNP-A-based genomic complexity and identifies among them the genomic characteristics most associated with types of response to intensive induction therapies and with shortened overall survival. This study is based on 156 patients with previously untreated AML for which paired tumor and normal samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays.