Dataset Information

Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score.

ABSTRACT:

Purpose

Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML.

Methods

Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older (≥ 60 years) cytogenetically normal (CN) patients with AML (n = 134). Genes with promoter DMRs and expression levels significantly associated with outcome were used to compute a prognostic gene expression weighted summary score that was tested and validated in four independent patient sets (n = 355).

Results

In the training set, we identified seven genes (CD34, RHOC, SCRN1, F2RL1, FAM92A1, MIR155HG, and VWA8) with promoter DMRs and expression associated with overall survival (OS; P ≤ .001). Each gene had high DMR methylation and lower expression, which were associated with better outcome. A weighted summary expression score of the seven gene expression levels was computed. A low score was associated with a higher complete remission (CR) rate and longer disease-free survival and OS (P < .001 for all end points). This was validated in multivariable models and in two younger (< 60 years) and two older independent sets of patients with CN-AML. Considering the seven genes individually, the fewer the genes with high expression, the better the outcome. Younger and older patients with no genes or one gene with high expression had the best outcomes (CR rate, 94% and 87%, respectively; 3-year OS, 80% and 42%, respectively).

Conclusion

A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.

SUBMITTER: Marcucci G

PROVIDER: S-EPMC3918538 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Publications

Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score.

Marcucci Guido G Yan Pearlly P Maharry Kati K Frankhouser David D Nicolet Deedra D Metzeler Klaus H KH Kohlschmidt Jessica J Mrózek Krzysztof K Wu Yue-Zhong YZ Bucci Donna D Curfman John P JP Whitman Susan P SP Eisfeld Ann-Kathrin AK Mendler Jason H JH Schwind Sebastian S Becker Heiko H Bär Constance C Carroll Andrew J AJ Baer Maria R MR Wetzler Meir M Carter Thomas H TH Powell Bayard L BL Kolitz Jonathan E JE Byrd John C JC Plass Christoph C Garzon Ramiro R Caligiuri Michael A MA Stone Richard M RM Volinia Stefano S Bundschuh Ralf R Bloomfield Clara D CD

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20131230 6

<h4>Purpose</h4>Molecular risk stratification of acute myeloid leukemia (AML) is largely based on genetic markers. However, epigenetic changes, including DNA methylation, deregulate gene expression and may also have prognostic impact. We evaluated the clinical relevance of integrating DNA methylation and genetic information in AML.<h4>Methods</h4>Next-generation sequencing analysis of methylated DNA identified differentially methylated regions (DMRs) associated with prognostic mutations in older ...[more]

PMID: 24378410

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Project description:Standard chemotherapy regimens for remission induction of pediatric acute myeloid leukemia (AML) are associated with significant morbidity and mortality. We performed a cohort study to determine the impact of reducing the intensity of remission induction chemotherapy on the outcomes of selected children with AML treated with a low-dose induction regimen plus granulocyte colony stimulating factor (G-CSF) (low-dose chemotherapy (LDC)/G-CSF). Complete response (CR) after two induction courses was attained in 87.0% (40/46) of patients receiving LDC/G-CSF. Post-remission therapy was offered to all patients, and included standard consolidation and/or stem cell transplantation. During the study period, an additional 94 consecutive children with AML treated with standard chemotherapy (SDC) for induction (80/94 (85.1%) of the patients attained CR after induction II, P = 0.953) and post-remission. In this non-randomized study, there were no significant differences in 4-year event-free (67.4 vs. 70.7%; P = 0.99) and overall (70.3 vs. 74.6%, P = 0.69) survival in the LDC/G-CSF and SDC cohorts, respectively. After the first course of induction, recovery of white blood cell (WBC) and platelet counts were significantly faster in patients receiving LDC/G-CSF than in those receiving SDC (11.5 vs. 18.5 d for WBCs (P < 0.001); 15.5 vs. 22.0 d for platelets (P < 0.001)). To examine the quality of molecular response, targeted deep sequencing was performed. Of 137 mutations detected at diagnosis in 20 children who attained hematological CR after two courses of LDC/G-CSF (n = 9) or SDC (n = 11), all of the mutations were below the reference value (variant allelic frequency <2.5%) after two courses, irrespective of the treatment group. In conclusion, children with AML receiving LDC/G-CSF appear to have similar outcomes and mutation clearance levels, but significantly lower toxicity than those receiving SDC. Thus, LDC/G-CSF should be further evaluated as an effective alternative to remission induction in pediatric AML.

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Dataset Information

Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score.

Purpose

Methods

Results

Conclusion

Publications

Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score.

Similar Datasets

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