Abstract 2757: NT5C2 single nucleotide polymorphisms affects survival and response in de novo AML patients with normal karyotype

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The nucleoside analog cytosine arabinoside (Cytosar®, AraC) is one of the corner stones in the treatment of acute myeloid leukemia (AML). Activated AraC is metabolized to inactive compounds by several intracellular enzymes. The levels of some of these enzymes have been correlated to effect of AraC and clinical outcome in patients with AML. This study was designed to evaluate if single nucleotide polymorphisms (SNPs) in genes coding for enzymes involved in the inactivation of AraC affects the therapeutic response in AML-patients treated with AraC in combination with anthracyclines. Three SNPs were investigated in 96 de novo AML patients with normal karyotype and correlated to response and overall survival. Two SNPs were located in the cytidine deaminase gene (CDA, A79C, rs2072671 and C-451T, [rs532545][1]), deaminating and inactivating AraC to its corresponding uridine derivative, AraU. The third SNP (A7G, rs10883841) was in the NT5C2 gene coding for the cytosolic 5′-nucleotidase II (cN-II), responsible for dephosphorylation and hence inactivation of AraC monophosphate. All SNPs were in Hardy-Weinberg equilibrium and the allele frequencies were 34.4, 34.4 and 18.8% for CDA A79C and C-451T, and NT5C2 A7G, respectively. Patients that were wild type (A/A) for NT5C2 A7G were found to have a borderline significant higher response rate (51 complete responders of 60 patients with A/A vs 20 complete responders of 30 with A/G or G/G, p=0.06) and longer survival (median survival 1.66 years compared to 0.87 years, log-rank p=0.08) compared to the rest of the patients. The two CDA SNPs (A79C, C-451T) were found to be in linkage disequilibrium. Although statistically not significant, patients that were found to be homozygous for the alternate genetic variant of the CDA SNP had a shorter survival compared to patients carrying the wild type or heterozygous genetic variants. In conclusion, our findings suggest that certain NT5C2 (cN-II) genotypes might affect the survival after chemotherapy and may provide useful information for treatment strategies, classification and individualized chemotherapy, and eventually used as prognostic marker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2757. [1]: /lookup/external-ref?link_type=GEN&access_num=rs532545&atom=%2Fcanres%2F70%2F8_Supplement%2F2757.atom