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Molecular prognostic factors in cytogenetically normal acute myeloid leukemia.

ABSTRACT: Chromosomal abnormalities are detected in 50-60% of patients with acute myeloid leukemia (AML) and are important predictors of prognosis and risk of relapse. The remaining patients, those with cytogenetically normal AML, are a seemingly homogeneous group that in fact consists of subsets of patients with distinct clinical outcomes. This heterogeneity is likely related to acquired gene mutations, as well as altered miRNA and gene-expression profiles, which occur within the group. The identification of recurrent molecular abnormalities has improved prognostication and provided insight into mechanisms of leukemogenesis for patients with cytogenetically normal AML, as well as led to the discovery of novel therapeutic targets. As the number of mutations continues to expand, bioinformatic algorithms that allow for integration of multiple markers will be necessary to provide optimal care for patients with this disease.

SUBMITTER: Walker A

PROVIDER: S-EPMC3582378 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Molecular prognostic factors in cytogenetically normal acute myeloid leukemia.

Walker Alison A Marcucci Guido G

Expert review of hematology 20121001 5

Chromosomal abnormalities are detected in 50-60% of patients with acute myeloid leukemia (AML) and are important predictors of prognosis and risk of relapse. The remaining patients, those with cytogenetically normal AML, are a seemingly homogeneous group that in fact consists of subsets of patients with distinct clinical outcomes. This heterogeneity is likely related to acquired gene mutations, as well as altered miRNA and gene-expression profiles, which occur within the group. The identificatio ...[more]

PMID: 23146058

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Project description:BACKGROUND:Aberrant DNA methylation is known to occur in patients with acute myeloid leukemia (AML), whereas methylation signatures and prognostic markers have been proposed. The objective of the current study was to evaluate all CpG sites of the genome and identify prognostic methylation markers for overall survival in patients with AML with normal karyotype (AML-NK). METHODS:AML-NK samples from 7 SWOG trials were analyzed using a novel genome-wide approach called "CHARMcox" (comprehensive high-throughput array-based relative methylation analysis combined with the Cox proportional hazards model) controlling for known clinical covariates. CHARMcox was applied to a phase 1 discovery cohort (72 patients) to identify survival-associated methylation regions (SAMRs). Subsequently, using bisulfite pyrosequencing, SAMRs were studied in phase 2 model-building (65 patients) and phase 3 validation (65 patients) cohorts. An independent external cohort from The Cancer Genome Atlas (TCGA) AML study (LAML) was used for further validation (93 patients). RESULTS:Two SAMRs, located at the CpG island shores of leucine zipper tumor suppressor 2 (LZTS2) and nuclear receptor subfamily 6 group a member 1 (NR6A1), respectively, were identified. Multivariable analyses demonstrated that hypomethylation of either LZTS2 or NR6A1 was associated with worse overall survival in the SWOG cohort (P<.001). The prognosis was validated in patients with AML-NK from the TCGA-LAML cohort. Methylation values below the median at both markers predicted worse overall survival (SWOG: hazard ratio, 1.89 [P<.001]; and TCGA-LAML: hazard ratio, 2.08 [P=.006]). The C-statistic was 0.71 for both cohorts, and the impact was independent of the Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) status. CONCLUSIONS:The 2 methylation markers, measurable by clinically applicable assays such as bisulfite pyrosequencing, are promising for risk stratification among patients with AML-NK. Cancer 2017;123:2472-81. © 2017 American Cancer Society.

Project description:BACKGROUND: Prognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia. DESIGN AND METHODS: Janus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent. RESULTS: The morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P = 0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P = 0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P = 0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P = 0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P = 0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P = 0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P = 0.024) and overall survival (P = 0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype. CONCLUSIONS: Janus kinase 2 46/1 haplotype influences morphological distribution, increasing the predisposition towards an acute myelomonocytoid form. It may be a novel, independent unfavorable risk factor in acute myeloid leukemia with a normal karyotype.

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Molecular prognostic factors in cytogenetically normal acute myeloid leukemia.

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Molecular prognostic factors in cytogenetically normal acute myeloid leukemia.

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