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Multi-genetic basis for prognostication in acute myeloid leukemia with aberrant and prognostically intermediate karyotypes as determined by gene expression profiling

Multi-genetic basis for prognostication in acute myeloid leukemia with aberrant and prognostically intermediate karyotypes as determined by gene expression profiling

Blood 102(11): 190b, November 16

The karyotype defines the biology of distinct subtypes in acute myeloid leukemia (AML) and is the most important prognostic factor. However, the cytogenetically based classification of AML reveals a large group with prognostically intermediate or undetermined karyotypes. Within these cases those without chromosomal aberrations may be further characterized by molecular genetic alterations like length mutations of the FLT3 gene or partial tandem duplication of the MLL gene. These mutations are present in half of these patients and have been proven prognostically relevant. In contrast, for patients with aberrant and prognostically intermediate and undetermined karyotype no genetic markers have been capable of predicting the patients' outcome. Using Affrymetrix U113A+B microarrays we determined the expression status of more than 30,000 genes in 25 patients with AML and karyotype aberrations rated as prognostically intermediate and undetermined (median age 55 years, range 18-77). Karyotype abnormalities included trisomy 8 as sole abnormality (n=7), inv(3) or t(3;3) (n=6), trisomy 13 (n=2), trisomy 13 (n=2), and trisomy 4, t(1;3), t(6;9), der(5)t(5;11), i(17), del(9q), del(12p), del(20q) (n=1 for each aberration). All patients were uniformly treated within the 1999 trial of the German AMLCG (TAD/HAM or HAM/HAM double induction therapy, TAD consolidation therapy, maintenance therapy). Median event-free survival (EFS) was 3.1 months and median overall survival (OS) was 20.7 months. The clinical parameters age, WBC count, hemoglobin level, and thrombocyte count were not related to either EFS or OS. Univariate Cox regression analyses were performed to identify genes significantly related to EFS and OS. Among the top 50 genes/transcripts related to EFS five were identified by multivariate analysis to independenty influence EFS: PRAME (p=0.037); human BRCA2 region, mRNA sequence CG006 (p=0.042); Homo sapiens cDNA: FLJ22765 fis, clone KAIA1180 (p=0.031); Homo sapiens cDNA FLJ36837 fis, clone ASTRO2011422 (p=0.032); and ESTs (p=0.049). A score was defined based on the expression status of these genes. This score revealed three groups (0 out of 5 vs. 1 to 3 out of 5 vs. 4 to 5 out of 5 genes expressed) with significantly differing EFS (75% at 1 year vs. median 3.1 months vs. median 1.2 mouths, p<0.0001). This score also resulted in significant differences in OS (100% at 1 year vs. median 20.7 months vs. median 1.7 months, p=0.0148). To check for the consistency of these prognostic genes within AML with aberrant and prognostically intermediate karyotypes 25 additional cases with other aberrations were analyzed (monosomy 7 n=6, t(3;21) n=1, t(6;9) n=1, del(5q) n=2, del(9q) n=2, inv(3) and monosomy 7 n=2, t(3;3) and t(5;17) n=1, trisomy 11 n=3, trisomy 13 n=5, trisomy 8 n=2). However, the score had no prognostic impact in this cohort. These data demonstrate that prognostically relevant genes may be identified in AML cases in which at present no prognostic markers are available. It is suggested that a combination of the expression status of multiple genes is necessary to accomplish prognostication which is in line with the concept of a multi-genetic basis of the leukemogenesis in these cases. Furthermore, it is suggested that for optimizing the performance of genetically based prognostic scores these should be applied only to cytogenetically homogeneous cohorts.

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Accession: 035349236

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