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

Autor:	Marcucci G; Guido Marcucci, Pearlly Yan, Kati Maharry, David Frankhouser, Deedra Nicolet, Klaus H. Metzeler, Jessica Kohlschmidt, Krzysztof Mrózek, Yue-Zhong Wu, Donna Bucci, John P. Curfman, Susan P. Whitman, Ann-Kathrin Eisfeld, Jason H. Mendler, Sebastian Schwind, Heiko Becker, John C. Byrd, Ramiro Garzon, Michael A. Caligiuri, Stefano Volinia, and Clara D. Bloomfield, The Ohio State University Comprehensive Cancer Center; Ralf Bundschuh, The Ohio State University, Columbus, OH; Kati Maharry, Deedra Nicolet, and Jessica Kohlschmidt, Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Maria R. Baer, Greenebaum Cancer Center, University of Maryland, Baltimore, MD; Meir Wetzler, Roswell Park Cancer Institute, Buffalo; Jonathan E. Kolitz, Monter Cancer Center, Lake Success, NY; Thomas H. Carter, University of Iowa, Iowa City, IA; Bayard L. Powell, The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC; Richard M. Stone, Dana-Farber Cancer Institute, Boston, MA; Constance Bär and Christoph Plass, German Cancer Research Center, Heidelberg, Germany., Yan P, Maharry K, Frankhouser D, Nicolet D, Metzeler KH, Kohlschmidt J, Mrózek K, Wu YZ, Bucci D, Curfman JP, Whitman SP, Eisfeld AK, Mendler JH, Schwind S, Becker H, Bär C, Carroll AJ, Baer MR, Wetzler M, Carter TH, Powell BL, Kolitz JE, Byrd JC, Plass C, Garzon R, Caligiuri MA, Stone RM, Volinia S, Bundschuh R, Bloomfield CD
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2014 Feb 20; Vol. 32 (6), pp. 548-56. Date of Electronic Publication: 2013 Dec 30.
DOI:	10.1200/JCO.2013.50.6337
Abstrakt:	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.
Databáze:	MEDLINE
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