Abstract PL07-01: Linkage disequilibrium-based analysis of DNA repair and GST genes in malignant gliomas: A unique tool in defining the association between genetic diversity and survival

Inherited genetics are increasingly being identified as a significant factor that contributes to both treatment outcome and treatment-associated toxicities in cancer patients undergoing therapy. The specific SNPs and genes involved are, however, still poorly understood. In this study, we exploited the unique advantages of a linkage disequilibrium-based approach to examine the relationship between genetic diversity in regions of DNA repair and GST genes with survival in adults with anaplastic astrocytoma and glioblastoma multiforme treated on temozolomide and carmustine-based protocols. We genotyped a subset of 1,267 tagging SNPs within or near haplotype blocks of 27 genes in 301 patients. The SNPs were selected to be in high LD with and, thus, to be predictive of the diversity of the target region containing the gene and 20 kb flanking 3′ and 5′ of it. Genotyping was conducted on a high-throughput customized Affymetrix platform. Associations between genotypes and survival was performed using the Fisher9s exact test, after testing for Hardy-Weinberg conformity and gender mismatches. The results identified several tSNPs in and around the loci of 11 genes (EXO1, DDB2, LIG1, MGMT, MSH2, MSH4, PAN3, RAD52, TDG, XRCC1, and XRCC5) to be highly associated with survival. Several other SNPs showing a statistical tendency to be associative. Although, a number of SNPs/genes was associated with survival in both anaplastic astrocytoma and GBM, a subset of genes and SNPs were associative in GBMs but not in AAs and vice versa. We then examined 28 SNPs in all eight members of the GST family (A1, M1, M3, P1, O1, S1, T and Z) allowing the identification of seven specific SNPs that were highly associated with treatment outcome/survival. The identification of highly polymorphic regions associated with the loci of DNA repair and GST genes as determinants of alkylating agent-based therapy in malignant gliomas is consistent with the established role of enhanced DNA repair and drug metabolism in tumor resistance to these agents. Ongoing studies are directed at these associative SNPs to gain insight into the biology underlying their association with treatment outcome. Supported by grants RO1 CA 153050, RO1 CA127872, RO1 CA 112519 and P30-CA114236 from the NIH, USA. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL07-01.