Predictive impact of genetic polymorphisms in DNA repair genes on susceptibility and therapeutic outcomes to colorectal cancer patients

Abstract

Several hereditary syndromes characterized by defective DNA repair are associated with high risk of colorectal cancer (CRC). To explore whether common polymorphisms in DNA repair genes affect risk and prognosis of CRC, we evaluated the association between single nucleotide polymorphisms (SNPs) in XPG, XPC, and WRN gene and susceptibility of CRC, and clinical outcomes in a population-based case-control study. A total of 890 CRC cases and 910 controls recruited into the study provided a biologic sample. Individuals with variant genotypes of XPC Ala499Val appeared to be associated with the increased risk of CRC. WRN Cys1367Arg variants carriers showed an increased susceptibility for CRC. More importantly, the risk of CRC increased further in a combined analysis of multiple polymorphisms. Furthermore, stratified analyses revealed that XPG Arg1104His polymorphism was associated with tumor differentiation of CRC patients (P = 0.043). Log-rank test and adjusted multivariate Cox regression analysis verified that XPG Arg1104His variants were associated with a longer disease-free survival (DFS) [CG genotype: adjusted HR (95% confidence interval (CI)) = 0.163 (0.107-0.248), P < 0.001; CC genotype: adjusted HR (95% CI) = 0.333 (0.235-0.470), P < 0.001; CG/CC genotype: adjusted HR (95% CI) = 0.333 (0.235-0.470)] in patients with oxaliplatin-based chemotherapy (N = 718). Moreover, XPC Ala499Val CT genotype showed a significant impact on DFS [CC genotype: adjusted HR (95% CI) = 0.691 (0.528-0.904), P = 0.007; CT/CC genotype: adjusted HR (95% CI) = 0.602 (0.389-0.934), P = 0.024]. However, no correlation was found between WRN Cys1367Arg polymorphism and prognosis in CRC patients. Our findings will add to the literature on the impact of genetic variation in DNA repair genes involved in susceptibility for CRC and therapeutic outcomes in response to oxaliplatin-based chemotherapy.

XPGrs2296147 T>C polymorphism predicted clinical outcome in colorectal cancer

“…Zhang et al [ 23 ] also reported that down-regulation of XPG activity caused by rs2296147 polymorphism was correlated with increased OS. There are a number of studies evaluating the influence of the XPG SNPs on the risk and therapeutic response of CRC [ 15 , 24 – 26 ]; however few have explored the association of XPG SNPs with the prognosis of CRC patients. CRC is one of the most common cancer worldwide, with approximately 55% of the cases occurring in the developed regions.…”

Recent Advances in Understanding Werner Syndrome

“…Primary tumors of colorectal cancer patients and cell lines display decreased WRN mRNA and protein expression 90 , 91 ; however, no WRN mutations have been associated with colorectal cancer risk 92 , 93 . Irinotecan (CPT-11), a semi-synthetic derivative of CPT, which is routinely used in colorectal cancer therapy, enhances the survival of colorectal cancer patients with hypermethylated WRN promoter 90 .…”

Predictive Biomarkers in Colorectal Cancer: From the Single Therapeutic Target to a Plethora of Options

“…Moreover, the combination of ERCC1-118 T/T genotype with either XPD-751 A/C or XPD-751 C/C resulted in an even shorter PFS (HR, 2.84; 95% CI, 1.47–0.45; p = 0.002), compared to the case when only one of these genotypes was present [ 46 ]. More recently, another study showed that the XPG Arg1104His polymorphism variants were associated with a longer DFS in patients receiving oxaliplatin-based chemotherapy [ 47 ]. Based on current data, ERCC1 screening is not recommended to select patients for oxaliplatin-based regimens.…”