DNA Repair Gene Polymorphisms and Chromosomal Aberrations in Exposed Populations

Yasmeen Niazi; Hauke Thomsen; Bozena Smolkova; Ludmila Vodickova; Sona Vodenkova; Michal Kroupa; Veronika Vymetalkova; Alena Kazimirova; Magdalena Barancokova; Katarina Volkovova; Marta Staruchova; Per Hoffmann; Markus M Nöthen; Maria Dusinska; Ludovit Musak; Pavel Vodicka; Kari Hemminki; Asta Försti

doi:10.3389/fgene.2021.691947

DNA Repair Gene Polymorphisms and Chromosomal Aberrations in Exposed Populations

Front Genet. 2021 Jun 16:12:691947. doi: 10.3389/fgene.2021.691947. eCollection 2021.

Authors

Yasmeen Niazi^{1

2

3}, Hauke Thomsen^{1

4}, Bozena Smolkova⁵, Ludmila Vodickova^{6

7

8}, Sona Vodenkova⁶, Michal Kroupa^{6

8}, Veronika Vymetalkova^{6

7

8}, Alena Kazimirova⁹, Magdalena Barancokova⁹, Katarina Volkovova⁹, Marta Staruchova⁹, Per Hoffmann^{10

11}, Markus M Nöthen¹⁰, Maria Dusinska¹², Ludovit Musak¹³, Pavel Vodicka^{6

7

8}, Kari Hemminki^{1

8

14}, Asta Försti^{1

2

3}

Affiliations

¹ Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
³ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
⁴ GeneWerk GmbH, Heidelberg, Germany.
⁵ Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Bratislava, Slovakia.
⁶ Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czechia.
⁷ First Faculty of Medicine, Institute of Biology and Medical Genetics, Charles University, Prague, Czechia.
⁸ Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Prague, Czecia.
⁹ Department of Biology, Faculty of Medicine, Slovak Medical University, Bratislava, Slovakia.
¹⁰ Institute of Human Genetics, School of Medicine and University Hospital Bonn, University of Bonn, Bonn, Germany.
¹¹ Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
¹² Health Effects Laboratory, Department of Environmental Chemistry, NILU-Norwegian Institute for Air Research, Kjeller, Norway.
¹³ Jessenius Faculty of Medicine, Biomedical Center Martin, Comenius University in Bratislava, Bratislava, Slovakia.
¹⁴ Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.

Abstract

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.

Keywords: DNA repair; association study; chromosomal aberrations; exposure; polymorphism.