Project description: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.

Project description:Background. B-Acute lymphoblastic leukemia (B-ALL) represents a hematologic malignancy with poor clinical outcome and low survival rates in adult patients. Only 61% of Colombian adult patients with ALL achieve complete remission and a median overall survival of less than 11.3 months and event-free survival of 7.34 months. Identification of prognostic factors is crucial for proper treatment strategies and optimal results of therapy. The goal of our study was to determine if gene expression signatures correlate with response to therapy and to evaluate the utility of these as prognostic tools for survival to better predict patient risk prior to therapy. Methods and findings. This study included 43 adult patients newly diagnosed with B-cell precursor or common B-ALL. Through microarray gene expression profiles, we identified 442 genes differentially expressed between 27 leukemia patients who responded or not to induction chemotherapeutic treatment. Hierarchical analysis with the 99 most differentially expressed genes between the two groups revealed 3 sets of patients that differed in their clinical characteristics, giving these genes high prognostic clinical outcome impact. We validated the expression of 7 genes by RT-PCR in 43 patients, and in addition to finding a correlation with gene expression profiles, we established correlations with good and poor prognosis from the time of diagnosis. Conclusions. Our study suggests that the response to induction treatment and clinical outcome of patients can be predicted from the onset of the disease and that gene expression profiles can be used to stratify patient risk adequately and accurately. The present study represents the first that shows that gene expression profiling could become a clinically relevant tool for stratification in the early course of disease of Colombian adults B-ALL. Stem cells from bone marrow samples from B-acute lymphoblastic leukemia (B-ALL) patients responding or not to the inductive therapy were isolated by sorting, and the gene expression was compared between the two groups. This submission includes samples from 27 B-ALL patients and 3 healthy individuals.

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