In this relatively large case-control study of 596 CRC patients and 300 controls, we assessed the influence of genetic polymorphisms on CRC risk, treatment toxicity, and survival in CRC patients. The patient cohort was well-monitored with a follow-up period of at least 5 years.
Polymorphisms and cancer risk
Data regarding the association between the investigated polymorphisms and CRC risk are controversial, which to a large extent is related to variability among populations. For each gene polymorphism, the minor allele varies greatly among ethnic groups. As an example, the XRCC1-rs25487 A allele ranges from 0.11 in the African population to 0.37 in European population , hence possibly contributing to different levels of susceptibility to CRC across populations. While previous studies on XRCC1-rs25487 confirmed the association of increased risk for CRC in particular among East Asians and Arab ethnicity [23–26], two meta-analysis studies, consistent with our results, suggested no association of this SNP and risk of CRC [27, 28]. Further large and well characterized studies, therefore, are needed to identify the association between the XRCC1-rs25487 polymorphism and CRC risk and how it varies in different populations.
Some Chinese [24, 29] and Norwegian  studies assessed the ERCC1-rs11615 polymorphism and CRC risk but found no significant correlations , in accordance with the findings of the present study. In contrast, a study of a Chinese population showed that the ERCC1-rs11615 genotype T/T contributed to a 1.9-fold increased CRC risk compared to CC genotype .
Our findings indicate that the A allele of ERCC2-rs238406 and the C allele of ERCC2-rs13181 have significantly increased risk of CRC which supports the study suggesting that the rs13181 heterozygote is linked to higher risk of CRC compared to TT or GG genotypes in a Spanish population . Moreover, the risk of CRC was significantly increased with the ERCC2-rs13181 A allele in one Romanian study . However, some studies conclude on the contrary that the CC genotype is associated with decreased CRC risk in American  and Iranian  populations. Furthermore, many studies, including one meta-analysis, which assessed the relation between the ERCC2-rs13181 polymorphism and CRC risk in multiple populations failed to find any link [37, 38]. Thus, more knowledge on the mechanisms of the ERCC2 variants is needed to clarify the implications of the present data.
Polymorphisms and toxicity
Treatment induced toxicity is an important factor that eventually can result in either dose reduction or termination of the treatment . In our study patients receiving FLV or oxaliplatin-based adjuvant therapy, the ERCC1-rs11615 genotype T/T was significantly associated with stomatitis, while among patients receiving first-line chemotherapy, the ERCC1-rs11615 C allele was associated with nausea. However, we could not find any association between ERCC1-rs11615 and haematological toxicity, as has been reported in other studies. For instance, one study reported the ERCC1-rs11615 genotype T/T to be correlated with severe leukopenia in patients with non-small lung cancer receiving platinum-based therapy in a Chinese population .
The ERCC1-rs11615 T allele has been shown to be linked with reduced response to treatment and poor OS in Asians, probably due to high expression of ERCC1 , and may be a predictive factor for CRC patients treated with oxaliplatin and 5-FU combined . Nevertheless, currently the European Society for Medical Oncology guidelines are against the use of ERCC1 expression status in therapeutic decisions on oxaliplatin use in routine clinical practice due to inconsistent results .
In our study, significantly more patients with the ERCC2-rs13181 C allele had eye reactions, thrombocytopenia, and needed dose reduction more often compared to patients with the A/A genotype. Haematological toxicity was also reported in a previous study, where the ERCC2-rs13181 C allele was significantly associated with an increased risk of FOLFOX-induced toxicity . We also find indications that the ERCC2-rs238406 C/C genotype is associated with a higher frequency of thrombocytopenia.
No association between XRCC1 polymorphism and any of the investigated toxicity parameters was found here. Our results are also consistent with the literature in failing to identify a significant prognostic effect of the XRCC1 SNP in metastatic CRC patients. Taken together we find no strong association of XRCC1 genotype with clinical outcome [44–46]. Nonetheless, other studies have shown that CRC patients who carry at least one A allele were at an increased risk of resistance to oxaliplatin-based treatment [47, 48].
Discrepancies regarding the association between polymorphisms and toxicity among studies might in addition to being population-dependent, be due to gender differences as reported in a recent publication by Ruzzo et al. . However, the impact of gender could not be assessed in our study due to the relatively small number of patients in each toxicity subgroup. The type of chemotherapy given may also affect the results and larger more homogenous groups in terms of treatment regimens and gender distribution may provide stronger data.
In general, neither 5-year RFS or OS were associated with any of the polymorphisms in the present study with the exception of the ERCC2-rs238406 C allele that was associated with significantly shorter 5-year OS among stage I and II CRC patients. Our results are in agreement with one study in Nordic population that showed patients with the ERCC2-rs238406 A/A genotype had a significantly longer progression-free survival compared to patients with the C/A and C/C genotypes . There was no significant difference, however, in the OS. Indeed, this polymorphism may reduce ERCC2 protein levels by altering mRNA stability  and a reduced ERCC2 protein activity in patients with the ERCC2-rs238406 the A/A genotype may lead to an increased sensitivity to DNA-damaging drugs like oxaliplatin and therefore a better progression-free survival .
According to the literature, the ERCC2-rs13181 has been shown to be a prognostic predictor for CRC  and one American study showed that CRC patients carrying the ERCC2-rs13181 C/C genotype displayed poor survival . Furthermore, a meta-analysis indicated that the ERCC2-rs13181 C allele was linked with poorer OS in Caucasians . The same study reported that the ERCC1-rs11615 T allele was associated with shorter OS in the oxaliplatin-treated Asians CRC patients . Likewise, the prognostic effect of the XRCC1 polymorphism has been confirmed with shorter disease-free survival in patients with A/A genotype , yet, other studies failed to identify any significant association of this SNP with cancer-specific or disease-free survival in CRC patients [44–46, 52].
Although the present study is relatively large, the number of patients is still too small to permit robust analysis in selective sub-groups. For instance, it would be interesting to study the impact of gene variants in stage III and stage IV patients grouped by different treatment regimens. However, we used a well-defined patient cohort with a long follow-up time which provided potentially clinically reliable information.