title: Epigenetics meets genetics in acute myeloid leukemia: clinical impact of a novel seven-gene score.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  A seven-gene score encompassing epigenetic and genetic prognostic information identifies novel AML subsets that are meaningful for treatment guidance.
authors.affiliation: 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.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Pearlly
authors.initials: P
authors.lastname: Yan
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: David
authors.initials: D
authors.lastname: Frankhouser
authors.forename: Deedra
authors.initials: D
authors.lastname: Nicolet
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.forename: Jessica
authors.initials: J
authors.lastname: Kohlschmidt
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mrózek
authors.forename: Yue-Zhong
authors.initials: YZ
authors.lastname: Wu
authors.forename: Donna
authors.initials: D
authors.lastname: Bucci
authors.forename: John P
authors.initials: JP
authors.lastname: Curfman
authors.forename: Susan P
authors.initials: SP
authors.lastname: Whitman
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
authors.forename: Jason H
authors.initials: JH
authors.lastname: Mendler
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.forename: Constance
authors.initials: C
authors.lastname: Bär
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carroll
authors.forename: Maria R
authors.initials: MR
authors.lastname: Baer
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Carter
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Ralf
authors.initials: R
authors.lastname: Bundschuh
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003561:Cytarabine / Q000008:administration & dosage; D019175:DNA Methylation; D003630:Daunorubicin / Q000008:administration & dosage; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D012720:Severity of Illness Index
chemical_list: D003561:Cytarabine; D003630:Daunorubicin