title: DNA methylation analysis of ALOX12 and GSTM1 in acute myeloid leukaemia identifies prognostically significant groups.
abstract: To determine the role of DNA methylation in the progression of acute myeloid leukaemia (AML), we analysed the methylation status of ALOX12, GSTM1, HS3ST2 and FZD9 in 127 AML patients. Aberrant methylation of ALOX12 was associated with the subcategory AML with myelodysplasia-related changes (P = 0·0439) and specifically with megakaryocytic dysplasia (P = 0·0003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P = 0·0469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 2·57 and 1·86, respectively. Furthermore, the significance of methylation of GSTM1 in predicting poor prognosis was maintained within the subcategories of AML not otherwise specified (NOS), AML with intermediate cytogenetic risk and normal karyotype AML. Finally, patients with both GSTM1 and ALOX12 methylated, demonstrated worse outcomes when all AML patients were assessed (OS; P = 0·000411) as well as within AML NOS (DFS; P = 0·0023), AML with intermediate cytogenetic risk (OS; P = 0·0104) and normal karyotype AML (OS; P = 0·00636). This study implicates methylation of specific genes in the classification and prognostication of AML and suggests that the morphological feature of multilineage dysplasia may be a surrogate marker of gene methylation in at least a subset of AML cases.
authors.affiliation: Department of Pathology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ohgami
authors.forename: Lisa
authors.initials: L
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.forename: Olga K
authors.initials: OK
authors.lastname: Weinberg
authors.forename: Mahesh
authors.initials: M
authors.lastname: Seetharam
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gotlib
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Arber
mesh_terms: D059786:Abnormal Karyotype; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D001092:Arachidonate 12-Lipoxygenase; D051157:Frizzled Receptors; D005982:Glutathione Transferase; D009363:Neoplasm Proteins; C549560:FZD9 protein, human; C476558:ALOX12 protein, human