Abstract LB-228: Association of XRCC1 SNPs with clinical response in AML patients

Abstract

Abstract DNA repair system is critical in maintaining genome stability and integrity in response to various exogenous and endogenous stress factors. It is a multistep processes involving several enzymes including XRCC1 (X-ray repair cross-complementing group1) protein which plays a vital role in DNA repair activities and therefore is important for maintenance of genetic stability. The current study involves investigation of single nucleotide polymorphisms (SNPs) in the XRCC1 gene and their association with clinical response in pediatric acute myeloid leukemia (AML) patients treated with cytarabine (ara-C) based anti-leukemic chemotherapy in the St. Jude AML02 clinical trial. The St. Jude AML02 trial enrolled 232 AML patients less than 22 years of age, randomized to receive induction I therapy containing high-dose cytarabine or low-dose cytarabine plus daunorubicin and etoposide. A total of eighteen XRCC1 SNPs were genotyped using MALDI-TOF based Sequenom assay and screened for association with 3 endpoints, namely: in vitro ara-C LC50 determined in leukemic cells obtained at diagnosis (which was measured by treating leukemic cells in vitro with varying concentrations of ara-C), event free survival (EFS) and overall survival (OS). Jung statistic was used to determine association of the number of minor alleles with EFS and OS. Association of genotypes with EFS and OS was measured using Cox regression models while considering previously identified prognostically important variables. Our results showed significant association of 4 XRCC1 SNPs with survival and ara-C LC50 in pediatric AML patients. Three of these were present in the coding region, while one was a regulatory SNP located in the promoter region of the XRCC1 gene. XRCC1 SNPs have also been shown to be associated with cancer susceptibility and survival in previous studies. Our results now demonstrate clinical significance of XRCC1 SNPs in pediatric AML and suggest a role of these SNPs as prognostic factors in AML chemotherapy. These results might open up opportunities for tailored chemotherapy based on genomic markers to improve therapeutic outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-228. doi:1538-7445.AM2012-LB-228