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

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Abstract

Purpose: Promoter hypermethylation of, for example, tumor-sup pressor 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-beta-D-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (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 alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with 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.

Details

Authors
  • Michael Grovdal
  • Rasheed Khan
  • Anni Aggerholm
  • Petar Antunovic
  • Jan Astermark
  • Per Bernell
  • Lena-Varia Engstroem
  • Lars Kjeldsen
  • Olle Linder
  • Lars Nilsson
  • Anna Olsson
  • Jonas Wallvik
  • Jon Magnus Tangen
  • Gunnar Oberg
  • Sten Eirik Jacobsen
  • Peter Hokland
  • Anna Porwit
  • Eva Hellstrom-Lindberg
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)7107-7112
JournalClinical Cancer Research
Volume13
Issue number23
Publication statusPublished - 2007
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012), Emergency medicine/Medicine/Surgery (013240200)