Acute myeloid leukemia outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients.
In acute myeloid leukemia (AML), cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to interindividual differences in DNA repair capacity, influencing outcome. We studied the role of six polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) in overall and disease-free survival among 170 adult de novo patients with intermediate cytogenetics (diploid [n = 117]; non-diploid [n = 53]), treated with induction chemotherapy. Kaplan-Meier and Cox proportional hazards models were performed. Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type genotype (median survival 22 vs. 40 months, p = 0.03). Diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type genotype (median survival 15 vs. 30 months, p = 0.02). After adjusting for clinical and sociodemographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying, compared to those with the wild-type genotypes (HR = 2.49; 95% CI: 1.06-5.85). No associations were observed for disease-free survival. This combined genotype may modulate treatment effect, decreasing overall survival. These findings could in the future help select treatments for patients with normal cytogenetics.
Strom
Sara S
SS
Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. sstrom@mdanderson.org
Estey
Elihu
E
Outschoorn
Ubaldo Martinez
UM
Garcia-Manero
Guillermo
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D056748:Cyclin H / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011379:Prognosis; D012307:Risk Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D055815:Young Adult; D000099250:DNA Excision Repair Protein ERCC-5
D056748:Cyclin H; D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D014157:Transcription Factors; D051759:Xeroderma Pigmentosum Group D Protein; D000099250:DNA Excision Repair Protein ERCC-5; C534751:CCNH protein, human; C086984:XPC protein, human; C071447:ERCC1 protein, human; C497292:ERCC2 protein, human