Abstract A107: Polymorphisms in nucleotide excision repair pathway and acute myeloid leukemia outcome Free

A107

Acute myeloid leukemia (AML), the most common leukemia in adults is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, AML patients are classified into favorable, intermediate and poor subgroups. Cytogenetics are good predictors of treatment outcome for the favorable and poor subgroups. However, for patients with intermediate cytogenetics, optimal treatment is uncertain. For these patients incorporating genetic markers to the existing prognostic factors might be helpful to identify subgroups of patients. Variants in genes within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity which could eventually influence AML outcome. We studied the role of 5 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, and CCNH Val270Ala) within this pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid karyotypes (n = 117) and non-diploid karyotypes (n = 53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. After a median follow-up of 16 months, 56% of diploid patients died compared to 71% among the non-diploid group (Log Rank p= 0.03). Among patients with diploid karyotypes, after adjusting for clinical and socio-demographic characteristics (age, sex, ethnicity, WBC, performance status, and smoking), XPD Lys751Gln and XPC Ala499Val were found to be independently associated with overall survival. Patients with the XPD Lys751Gln/Gln751Gln genotype were twice more likely to have died than those with the wild genotype (HR: 1.97; 95% CI: 1.09 - 3.55). XPC Ala499Val/Val499Val patients had a 75% increased mortality compared to those with the wild genotype (HR: 1.75; 95% CI: 1.02 - 2.98). Patients carrying both (XPD Lys751Gln/Gln751Gln and XPC Ala499Val/Val499Val) had significantly shorter survival compared to those with the wild genotype (HR: 3.49; 95% CI: 1.58 - 7.68). 21% of the AML patients with diploid cytogenetics carried both risk variants. No significant associations were observed for disease-free survival in AML patients. Our results suggest that polymorphic variants in NER repair enzymes may modulate AML outcome in patients with diploid cytogenetics. Patients with the high risk genotype combination could have diminished DNA repair capacity, which in turn, could result in greater susceptibility to genotoxic effects of treatment decreasing overall survival. These findings could in the future be used in selecting treatment strategies for patients with normal cytogenetics.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A107.