DNA Promoter Methylation Analysis of Acute Myeloid Leukemia: ALOX12 Methylation Correlates with Myelodysplasia-Related Changes While Methylation of ALOX12 and GSTM1 Correlate with Disease Progression and Worse Overall Survival.
Robert S Ohgami, Olga K Weinberg, Lisa N Ma, Li Ren, Mahesh Seetharam, Daniel A Arber. Stanford University Medical Center, CA
Background: While genetic mutational and structural aberrancies are well studied in AMLs; our understanding of the pathologic role of methylation of genes is less clear. Specifically, the significance of methylation, with regards to four genes, GSTM1, ALOX12, HS3ST2 and FZD9, which preliminarily have been linked to the progression of both epithelial and hematopoietic cancers, is not well defined.
Design: To determine the role of methylation in AML, we performed DNA promoter methylation analysis of these genes using a study set of 127 clinically well-defined AML patients.
Results: Methylation of ALOX12 was most frequent, found in 94 patients (74%) followed by GSTM1 in 36 (29%), HS3ST2 in 30 (24%), and FZD9 in 5 (4%). 27 patients (22%) showed methylation of both ALOX12 and GSTM1, 24 (19%) showed methylation of ALOX12 and HS3ST2, 6 (5%) showed methylation of HS3ST2 and GSTM1, and 5 (4%) showed methylation of ALOX12, HS2ST2 and GSTM1. Interestingly, log-rank test analysis demonstrated significant association between methylation of GSTM1 and worse overall survival (P = 0.0452) and progression free survival (P = 0.0441) (Figure 1). Importantly, these results were not associated with age, gender, white blood cell count, or blast count. Furthermore, combinatorial analysis of aberrant methylation of both ALOX12 and GSTM1 was associated with worse overall survival (P = 0.0023) and poor progression free survival (P = 0.0247) (Figure 2). Finally, we also demonstrate significant association of aberrant methylation of ALOX12 with the AML subcategory, AML with myelodysplasia related changes (P = 0.0439).
Conclusions: This study provides significant data implicating methylation of GSTM1, and ALOX12 in the progression of AML and subtyping of distinct categories.
Monday, February 28, 2011 2:00 PM
Platform Session: Section B, Monday Afternoon