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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.
Highlights
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer death worldwide [1]
We evaluated the association of 16 non-synonymous single nucleotide polymorphisms (nsSNPs) in 12 DNA repair genes with CRC risk, post-diagnosis survival, and therapy outcomes in a discovery set of 1832 patients and 1172 controls from the Czech Republic and in an independent replication set comprising 950 patients and 820 controls from Austria
The same nsSNPs were analyzed in the replication Austrian cohort, except for two nsSNPs (FAAP24 rs3816032 and MUS81 rs545500), where the genome-wide association study (GWAS) data were not available
Summary
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer death worldwide [1]. Treatment efficacy is influenced by the DNA repair capacity of cancer cells, and the differences in treatment response might be affected by the inherited variations of genes encoding DNA repair enzymes [15]. We hypothesized that SNPs causing amino acid substitution (non-synonymous SNPs—nsSNPs) in DNA repair genes that are known to be involved in maintaining genome stability (cancer prevention) and in chemotherapy response (cancer treatment), may influence CRC susceptibility and modulate the clinical outcome after cancer diagnosis. We evaluated the association of 16 nsSNPs in 12 DNA repair genes with CRC risk, post-diagnosis survival, and therapy outcomes in a discovery set of 1832 patients and 1172 controls from the Czech Republic and in an independent replication set comprising 950 patients and 820 controls from Austria
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