Comprehensive analysis of ERCC, XPD, and XRCC polymorphisms: Association with clinical outcomes in patients with advanced gastric cancer

Abstract

4649 Background: Platinum-DNA adducts are repaired by nucleotide excision repair (NER) pathway, in which genes of the excision repair cross-complementation 1 (ERCC1), xeroderma pigmentosum group D (XPD) and X-ray repair cross-complementing group (XRCC) have an important role. The purpose of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of these genes and the clinical outcomes to combination chemotherapy of 5-FU and oxaliplatin in advanced gastric cancer (AGC). Methods: We searched SNPs of NER pathway genes from database of the International Hapmap Project. Tagging SNPs and halpotype blocks were founded by linakage disequilibrium and haplotype analysis. Whole blood samples were obtained from the patients before chemotherapy. DNA was extracted from the peripheral blood mononuclear cells and the genotyping was performed by SNaPshot methods. Seventy three metastatic or relapsed AGC patients received modified FOLFOX-6 as a first-line palliative chemotherapy and were analyzed. Results: By searching the database of the International Hapmap Project, we found 17 SNPs in ERCC, 69 SNPs in XPD, 78 SNPs in XRCC. We found that some SNPs played a role as a tagging SNP and belonged to haplotype block (5 tapping SNPs and one haplotype block in ERCC, 8 tapping SNPs and two haplotype blocks in XPD, 9 tapping SNPs and two haplotype block in XRCC). Tagging SNPs were analyzed and matched with clinical significance. Among the 22 tagging SNPs of NER pathway genes, only XPD-C156A SNP (rs238406) showed clinical correlation. AA genotype of XPD C156A showed higher response rate (CC: CA: AA= 29.2%: 43.3%: 63.2%, p=0.083) and toxicities (neutropenia of grade 3 or 4) (CC: CA: AA= 4.3%: 3.2%: 21.1%, p=0.060) than CC or CA genotypes. Conclusions: Our results suggest that some SNPs of ERCC, XPD and XRCC showed linkage disequilibrium and belonged to haplotype blocks. And XPD-C156A SNP showed clinical correlation in AGC patients treated with modified FOLFOX-6 regimen. These findings require independent prospective confirmation. [Table: see text]