Functional Polymorphisms in DNA Repair Genes Are Associated with Sporadic Colorectal Cancer Susceptibility and Clinical Outcome

Abstract

DNA repair processes are involved in both the onset and treatment efficacy of colorectal cancer (CRC). A change of a single nucleotide causing an amino acid substitution in the corresponding protein may alter the efficiency of DNA repair, thus modifying the CRC susceptibility and clinical outcome. We performed a candidate gene approach in order to analyze the association of non-synonymous single nucleotide polymorphisms (nsSNPs) in the genes covering the main DNA repair pathways with CRC risk and clinical outcome modifications. Our candidate polymorphisms were selected according to the foremost genomic and functional prediction databases. Sixteen nsSNPs in 12 DNA repair genes were evaluated in cohorts from the Czech Republic and Austria. Apart from the tumor-node-metastasis (TNM) stage, which occurred as the main prognostic factor in all of the performed analyses, we observed several significant associations of different nsSNPs with survival and clinical outcomes in both cohorts. However, only some of the genes (REV3L, POLQ, and NEIL3) were prominently defined as prediction factors in the classification and regression tree analysis; therefore, the study suggests their association for patient survival. In summary, we provide observational and bioinformatics evidence that even subtle alterations in specific proteins of the DNA repair pathways may contribute to CRC susceptibility and clinical outcome.

Oxidative Damage in Sporadic Colorectal Cancer: Molecular Mapping of Base Excision Repair Glycosylases in Colorectal Cancer Patients

“…The NEIL3 encodes a DNA glycosylase involved in the first step of the BER pathway. Significantly elevated expression levels in tumors, compared to corresponding non-malignant tissues, were reported in 20 cancer sites, including CRC [99].…”

“…Despite all the efforts in CRC therapy over the years, 5-year survival remains unsatisfactory. The prognosis for CRC patients decreases with increasing TNM staging, the five-years survival rate is up to 90% for stage I, but only less than 15% for stage IV [99]. CRC treatment usually involves complete primary tumor resection and appropriate chemotherapy, which often causes severe adverse effects [124].…”

REV3L gene variants rs1002481, rs462779, and rs465646 lead to increased susceptibility towards non-small cell lung cancer in the population of Jammu and Kashmir.

“…The role of Rev3 in the maintenance of common fragile sites, further reinforces the role of TLS polymerases in cancer [30]. Consistent with their potential role in cancer, several studies have investigated the association of SNVs in these genes with different cancers, including lung cancer [18,22,31]. However, the association of TLS gene SNVs with any cancer in the population of J&K has not yet been studied.…”

REV3L Gene Variants rs1002481, rs462779, and rs465646 Lead to Increased Susceptibility Towards Non-Small Cell Lung Cancer in the Population of Jammu and Kashmir.

“…The role of Rev3 in the maintenance of common fragile sites, further reinforces the role of TLS polymerases in cancer [20]. Consistent with their potential role in cancer, several studies have investigated the association of SNVs in these genes with different cancers including lung cancer [21][22][23]. However, the association of TLS gene SNVs with any cancer in the population of J&K has not yet been studied.…”

“…22.13±3.75 kg/m 2 and of controls was 23.01±5.2 kg/m 2 (p-value=0.034). The distribution of other clinical characteristics between cases and controls are given in table 1.…”