DNA damage and unrepaired or insufficiently repaired DNA double-strand breaks as well as telomere shortening contribute to the formation of structural chromosomal aberrations (CAs). Non-specific CAs have been used in the monitoring of individuals exposed to potential carcinogenic chemicals and radiation. The frequency of CAs in peripheral blood lymphocytes (PBLs) has been associated with cancer risk and the association has also been found in incident cancer patients. CAs include chromosome-type aberrations (CSAs) and chromatid-type aberrations (CTAs) and their sum CAtot. In the present study, we used data from our published genome-wide association studies (GWASs) and extracted the results for 153 DNA repair genes for 607 persons who had occupational exposure to diverse harmful substances/radiation and/or personal exposure to tobacco smoking. The analyses were conducted using linear and logistic regression models to study the association of DNA repair gene polymorphisms with CAs. Considering an arbitrary cutoff level of 5 × 10-3, 14 loci passed the threshold, and included 7 repair pathways for CTA, 4 for CSA, and 3 for CAtot; 10 SNPs were eQTLs influencing the expression of the target repair gene. For the base excision repair pathway, the implicated genes PARP1 and PARP2 encode poly(ADP-ribosyl) transferases with multiple regulatory functions. PARP1 and PARP2 have an important role in maintaining genome stability through diverse mechanisms. Other candidate genes with known roles for CSAs included GTF2H (general transcription factor IIH subunits 4 and 5), Fanconi anemia pathway genes, and PMS2, a mismatch repair gene. The present results suggest pathways with mechanistic rationale for the formation of CAs and emphasize the need to further develop techniques for measuring individual sensitivity to genotoxic exposure.

1st Faculty of Medicine Institute of Biology and Medical Genetics Charles University Prague Czechia

Department of Biology Faculty of Medicine Slovak Medical University Bratislava Slovakia

Department of Molecular Biology of Cancer Institute of Experimental Medicine Czech Academy of Sciences Prague Czechia

Department of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Department of Molecular Oncology Cancer Research Institute Biomedical Research Center of the Slovak Academy of Sciences Bratislava Slovakia

Division of Cancer Epidemiology German Cancer Research Centre Heidelberg Germany

Division of Medical Genetics Department of Biomedicine University of Basel Basel Switzerland

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Prague Czecia

GeneWerk GmbH Heidelberg Germany

Health Effects Laboratory Department of Environmental Chemistry NILU Norwegian Institute for Air Research Kjeller Norway

Hopp Children's Cancer Center Heidelberg Germany

Institute of Human Genetics School of Medicine and University Hospital Bonn University of Bonn Bonn Germany

Jessenius Faculty of Medicine Biomedical Center Martin Comenius University in Bratislava Bratislava Slovakia

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