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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 syndrome
Grövdal, M., Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
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2007 (English)In: Clinical Cancer Research, ISSN 1078-0432, Vol. 13, no 23, 7107-7112 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS), however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. Experimental Design: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-ß-D-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15ink4b (P15), E-cadherin (CDH), and hypermethylated in cancer1 (HIC) genes were analyzed before treatment. Results: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02).Whereas P15 status alonewas not significantly associatedwith CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03).Moreover, patientswith CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. Conclusions: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group. © 2007 American Association for Cancer Research.

Place, publisher, year, edition, pages
2007. Vol. 13, no 23, 7107-7112 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-47510DOI: 10.1158/1078-0432.CCR-07-1193OAI: diva2:268406
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2011-01-11

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Antunovic, Petar
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