Polymorphisms in DNA repair pathway genes and gene in advanced colorectal cancer: correlation with tumor characteristics and clinical outcome in oxaliplatin-based chemotherapy.

OBJECTIVE

Multiple factors are involved in oxaliplatin-resistant process in colorectal cancer (CRC) patients including decreased drug accumulation and enhanced capacity to repair and tolerate DNA damage. In the present study, we aimed to assess the impact of six single-nucleotide polymorphisms (SNPs) in DNA repair genes and gene on prognosis in advanced CRC patients treated with oxaliplatin-based chemotherapy.

METHODS

In this study, 580 advanced CRC patients were recruited. Six SNPs of DNA repair genes ( rs10817938, rs2808668, rs2607775, and rs1346044) and gene (rs2231142 and rs2622621) were genotyped by using the TaqMan assay.

RESULTS

Regarding interaction with environmental factors, rs2231142 and the first-degree family history of cancer and rs2607775 or rs2622621 and lymph node metastases status demonstrated significant interactions. Of these six SNPs, rs10817938 CT/ TT genotypes retained its significant association with longer overall survival (OS) (=0.008) in CRC patients receiving oxaliplatin-based chemotherapy (n=580). Furthermore, a significantly better impact on the disease-free survival (DFS) (=0.001) and OS (<0.0001) was found in rs2231142CA/AA carriers. Furthermore, rs2622621 CG/GG genotype was verified to be an independent poor prognostic factor in DFS (=0.010) and OS (=0.030). In the stratification analysis, rs10817938 CT/CC, rs2231142 CA/AA, and rs2622621 CC genotypes of were predictive of significantly better prognosis in the patients with tumor differentiation grade 3 (n=523), clinical stage IV (n=73), or lymph node-positive status (n=557). Additionally, multivariate logistic regression and multiple dimension reduction analysis consistently revealed that the combination of selected SNPs and five known risk factors showed a better prediction prognosis and represented the best model to predict CRC prognosis.

CONCLUSION

The current data indicated that the gene and gene had significant interaction with environmental factors and prognosis, which could provide a comprehensive understanding of the implications of those SNPs in the prediction of prognosis in advanced CRC patients receiving oxaliplatin-based chemotherapy.