DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes
Open Access
- 1 February 2010
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 28 (4), 605-613
- https://doi.org/10.1200/jco.2009.23.4781
Abstract
Purpose The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS. Patients and Methods We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome. Results In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses. Conclusion DNA methylation predicts overall and progression-free survival in MDS.Keywords
This publication has 29 references indexed in Scilit:
- New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patientsBlood, 2007
- Negative Effect of DNA Hypermethylation on the Outcome of Intensive Chemotherapy in Older Patients with High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia following Myelodysplastic SyndromeClinical Cancer Research, 2007
- RIL, a LIM Gene on 5q31, Is Silenced by Methylation in Cancer and Sensitizes Cancer Cells to ApoptosisCancer Research, 2007
- Evolving classifications of the myelodysplastic syndromesCurrent Opinion in Hematology, 2007
- Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemiaBlood, 2006
- Decitabine improves patient outcomes in myelodysplastic syndromesCancer, 2006
- Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemiaLeukemia, 2003
- Analysis of Microarray Data Using Z Score TransformationThe Journal of Molecular Diagnostics, 2003
- Hematologic malignanciesCurrent Opinion in Hematology, 2001
- The establishment and maintenance of DNA methylation patterns in mouse somatic cellsSeminars in Cancer Biology, 1999