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.

Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague 323 00 Pilsen Czech Republic

Cancer Biology and Therapeutics Group UCD Conway Institute University College Dublin Dublin 4 Ireland

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruska 2411 87 100 00 Prague Czech Republic

Department of Medical Sciences University of Turin Corso Dogliotti 14 10126 Turin Italy

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer Hospital Videnska 800 140 59 Prague Czech Republic

Department of Surgery 1st Faculty of Medicine Charles University and Thomayer Hospital Thomayerova 815 5 140 00 Prague Czech Republic

Department of Surgery General University Hospital Prague U Nemocnice 499 2 128 08 Prague Czech Republic

Department of Surgery Medical School in Pilsen Charles University Alej svobody 80 304 600 Pilsen Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Albertov 4 128 00 Prague Czech Republic

Institute of Cancer Research Department of Medicine 1 Medical University of Vienna Borschkegasse 8a A 1090 Vienna Austria

Molecular and Genetic Epidemiology; Genomic Variation in Human Populations and Complex Diseases IIGM Italian Institute for Genomic Medicine Via Nizza 52 10126 Turin Italy

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