Abstract
Background: Methylation of tumor suppression genes (TSGs) is common in myeloid malignancies. However, application of this as a molecular marker for risk stratification in patients with AML is limited. Design and Methods: To elucidate the impact of patterns of TSG methylation on outcome in cytogenetically normal patients, 106 samples from patients with having normal cytogenetic AML were evaluated for methylation of 12 genes by MSP. For sake of comparison, samples from patients with AML and abnormal cytogenetics (n=63) were also evaluated. Results: Methylation frequencies in the whole group (n=169) were similar to previous reports for CDH1 (31%), ER (31%), FHIT (9%), p15INK4b (44%), p73 (25%), and SOCS1 (75%). Methylation of CTNNA1 was observed in 10%, CEBP-α in16%, CEBP-δ in 2%, MLH1 in 24%, MGMT in 11% and DAPK in 2% of AML samples. We find that DNA methylation was more prevalent in patients with normal compared to karyotypically abnormal AML for most genes; CEBPα (20% vs 9%), CTNNA1 (14% vs 4%), and ER (41% vs 19%) (p<0.05 for all comparisons). In contrast, p73 was more frequently methylated in patients with karyotypic abnormalities (17% vs 38%; p<0.05), perhaps due to specific silencing of the pro-apoptotic promoter shifting p73 gene expression to the anti-apoptotic transcript. In AML patients with normal cytogenetics, TSG methylation was not associated with event free or overall survival in a multivariate analysis. Conclusions: In patients with AML, TSG methylation is more frequent in patients with normal karyotype than those with karyotypic abnormalities but does not confer independent prognostic information for patients with normal cytogenetics.
Acknowledgements
This work was supported by The Flight Attendant Medical Research Institute (FAMRI), grant number 032053. MAM would like to acknowledge the Department of Defense (MPD510343) for support. This work was also supported by the NCI Cancer Center Support Grant (CA06793) which helped to support the Specimen Acquisition Core (SAC) Laboratory for sample collection and storage.
Conflict of Interest
Dr. James Herman is a consultant to and receives research support from OncoMethylome Sciences. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. All the other authors have no conflicts of interests to disclose.