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| IJMEG Copyright © 2010-present. All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711 |
Int J Mol Epidemiol Genet 2010;1(4):278-294.
Original Article
XPD DNA nucleotide excision repair gene polymorphisms associated with DNA
repair deficiency predict better treatment outcomes in secondary acute
myeloid leukemia
Nataliya Kuptsova-Clarkson, Christine B. Ambrosone, Joli Weiss, Maria R. Baer, Lara E. Sucheston, Gary Zirpoli, Kenneth J.
Kopecky, Laurie Ford, Javier Blanco, Meir Wetzler5, Kirsten B. Moysich
Department of Cancer Prevention and Control and Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA; presently at
Children’s Memorial Research Center, Children’s Memorial Hospital, Chicago, IL, USA; presently at Greenebaum Cancer
Center, University of Maryland School of Medicine, Baltimore, Maryland, USA; Southwest Oncology Group Statistical Center,
Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Pharmaceutical Sciences, University at Buffalo,
Buffalo, NY, USA.
Received May 18, 2010, accepted July, 2010, available online July, 2010
Abstract: DNA repair pathway pharmacogenetic studies have consistently demonstrated correlations between the XRCC1
Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes, associated with suboptimal DNA repair, and differential cancer
treatment outcomes. We evaluated these polymorphisms and XPD haplotypes in adult de novo (n=214) and secondary (n=79)
acute myeloid leukemia (AML) patients treated with cytarabine and anthracycline chemotherapy. Genotyping was performed by
MALDI-TOF mass spectrometry, and logistic and proportional hazards regression models were used to evaluate relationships.
Differential responses were observed in secondary, but not de novo, AML. Among secondary AML patients, the odds of
achieving complete remission (CR) were higher for XPD 312Asn/Asn XPD 751Gln/Gln (OR= 11.23; 95% CI, 2.23-56.63) and
XPD 751Gln/Gln (OR= 7.07; 95% CI, 1.42-35.18) genotypes. The BB diplotype was associated with CR attainment [OR=18.31;
95% CI: 2.08-283.57] and longer survival [HR=0.31; 95% CI: 0.14-0.73] compared to the referent AA diplotype. The XPD 751 CC,
312GA, 312AA genotypes and the XPD DC diplotype were also associated with longer overall survival (OS).Thus XPD codon
312 and 751 variant genotypes and haplotypes containing at least one variant allele may predict better treatment responses.
Impact: If validated, these findings could support stratification of chemotherapy in secondary AML. (IJMEG1005001).
Keywords: Acute myeloid leukemia (AML), secondary AML, pharmacogenetics/pharmacogenomics, DNA repair gene
polymorphisms
Full Text PDF
Address all correspondence to:
Kirsten B. Moysich, PhD
Roswell Park Cancer Institute
Elm & Carlton Sts.
Buffalo, NY 14263
Tel.: (716) 845 8004, Fax: (716) 845 8125,
E-mail: Kirsten.Moysich@roswellpark.org
Original Article
XPD DNA nucleotide excision repair gene polymorphisms associated with DNA
repair deficiency predict better treatment outcomes in secondary acute
myeloid leukemia
Nataliya Kuptsova-Clarkson, Christine B. Ambrosone, Joli Weiss, Maria R. Baer, Lara E. Sucheston, Gary Zirpoli, Kenneth J.
Kopecky, Laurie Ford, Javier Blanco, Meir Wetzler5, Kirsten B. Moysich
Department of Cancer Prevention and Control and Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA; presently at
Children’s Memorial Research Center, Children’s Memorial Hospital, Chicago, IL, USA; presently at Greenebaum Cancer
Center, University of Maryland School of Medicine, Baltimore, Maryland, USA; Southwest Oncology Group Statistical Center,
Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Pharmaceutical Sciences, University at Buffalo,
Buffalo, NY, USA.
Received May 18, 2010, accepted July, 2010, available online July, 2010
Abstract: DNA repair pathway pharmacogenetic studies have consistently demonstrated correlations between the XRCC1
Arg399Gln, XPD Lys751Gln and XPD Asp312Gln genotypes, associated with suboptimal DNA repair, and differential cancer
treatment outcomes. We evaluated these polymorphisms and XPD haplotypes in adult de novo (n=214) and secondary (n=79)
acute myeloid leukemia (AML) patients treated with cytarabine and anthracycline chemotherapy. Genotyping was performed by
MALDI-TOF mass spectrometry, and logistic and proportional hazards regression models were used to evaluate relationships.
Differential responses were observed in secondary, but not de novo, AML. Among secondary AML patients, the odds of
achieving complete remission (CR) were higher for XPD 312Asn/Asn XPD 751Gln/Gln (OR= 11.23; 95% CI, 2.23-56.63) and
XPD 751Gln/Gln (OR= 7.07; 95% CI, 1.42-35.18) genotypes. The BB diplotype was associated with CR attainment [OR=18.31;
95% CI: 2.08-283.57] and longer survival [HR=0.31; 95% CI: 0.14-0.73] compared to the referent AA diplotype. The XPD 751 CC,
312GA, 312AA genotypes and the XPD DC diplotype were also associated with longer overall survival (OS).Thus XPD codon
312 and 751 variant genotypes and haplotypes containing at least one variant allele may predict better treatment responses.
Impact: If validated, these findings could support stratification of chemotherapy in secondary AML. (IJMEG1005001).
Keywords: Acute myeloid leukemia (AML), secondary AML, pharmacogenetics/pharmacogenomics, DNA repair gene
polymorphisms
Full Text PDF
Address all correspondence to:
Kirsten B. Moysich, PhD
Roswell Park Cancer Institute
Elm & Carlton Sts.
Buffalo, NY 14263
Tel.: (716) 845 8004, Fax: (716) 845 8125,
E-mail: Kirsten.Moysich@roswellpark.org
