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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

Grovdal, Michael; Khan, Rasheed; Aggerholm, Anni; Antunovic, Petar; Astermark, Jan LU ; Bernell, Per; Engstroem, Lena-Varia; Kjeldsen, Lars; Linder, Olle and Nilsson, Lars LU , et al. (2007) In Clinical Cancer Research 13(23). p.7107-7112
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
13
issue
23
pages
7107 - 7112
publisher
American Association for Cancer Research
external identifiers
  • wos:000251529000026
  • scopus:37249040925
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-07-1193
language
English
LU publication?
yes
id
dc1e1ddd-18c6-4681-b863-7f7bd30508b0 (old id 966355)
date added to LUP
2008-01-29 15:20:17
date last changed
2017-10-29 03:36:52
@article{dc1e1ddd-18c6-4681-b863-7f7bd30508b0,
  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.},
  author       = {Grovdal, Michael and Khan, Rasheed and Aggerholm, Anni and Antunovic, Petar and Astermark, Jan and Bernell, Per and Engstroem, Lena-Varia and Kjeldsen, Lars and Linder, Olle and Nilsson, Lars and Olsson, Anna and Wallvik, Jonas and Tangen, Jon Magnus and Oberg, Gunnar and Jacobsen, Sten Eirik and Hokland, Peter and Porwit, Anna and Hellstrom-Lindberg, Eva},
  issn         = {1078-0432},
  language     = {eng},
  number       = {23},
  pages        = {7107--7112},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {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},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-07-1193},
  volume       = {13},
  year         = {2007},
}