Genomic instability is a characteristic of a majority of human malignancies. Chromosomal instability is a common form of genomic instability that can be caused by defects in mitotic checkpoint genes. Chromosomal aberrations in peripheral blood are also indicative of genotoxic exposure and potential cancer risk. We evaluated associations between inherited genetic variants in 33 mitotic checkpoint genes and the frequency of chromosomal aberrations (CAs) in the presence and absence of environmental genotoxic exposure. Associations with both chromosome and chromatid type of aberrations were evaluated in two cohorts of healthy individuals, namely an exposed and a reference group consisting of 607 and 866 individuals, respectively. Binary logistic and linear regression analyses were performed for the association studies. Bonferroni-corrected significant p-value was 5 × 10-4 for 99 tests based on the number of analyzed genes and phenotypes. In the reference group the most prominent associations were found with variants in CCNB1, a master regulator of mitosis, and in genes involved in kinetochore function, including CENPH and TEX14, whereas in the exposed group the main association was found with variants in TTK, also an important gene in kinetochore function. How the identified variants may affect the fidelity of mitotic checkpoint remains to be investigated, however, the present study suggests that genetic variation may partly explain interindividual variation in the formation of CAs.

Biomedical Center Martin Comenius University in Bratislava Jessenius Faculty of Medicine Malá Hora 03601 Martin Slovakia

Department of Biology Faculty of Medicine Slovak Medical University Limbova 12 833 03 Bratislava Slovakia

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 Molecular Genetic Epidemiology German Cancer Research Center Im Neuenheimer Feld 580 69120 Heidelberg Germany

Department of Molecular Oncology Cancer Research Institute Biomedical Research Center Slovak Academy of Sciences Dubravska cesta 9 84505 Bratislava Slovakia

Division of Cancer Epidemiology German Cancer Research Centre 69120 Heidelberg Germany

Division of Medical Genetics Department of Biomedicine University of Basel 4003 Basel Switzerland

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

GeneWerk GmbH Im Neuenheimer Feld 582 6910 Heidelberg Germany

Health Effects Laboratory Department of Environmental Chemistry NILU Norwegian Institute for Air Research Instituttveien 18 2007 Kjeller Norway

Hopp Children's Cancer Center Heidelberg Germany

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

Institute of Human Genetics University of Bonn School of Medicine and University of Bonn D 53127 Bonn Germany

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$a Niazi, Yasmeen $u Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: y.niazi@kitz-heidelberg.de

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$a Impact of genetic polymorphisms in kinetochore and spindle assembly genes on chromosomal aberration frequency in healthy humans / $c Y. Niazi, H. Thomsen, B. Smolkova, L. Vodickova, S. Vodenkova, M. Kroupa, V. Vymetalkova, A. Kazimirova, M. Barancokova, K. Volkovova, M. Staruchova, P. Hoffmann, MM. Nöthen, M. Dusinska, L. Musak, P. Vodicka, K. Hemminki, A. Försti

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$a Genomic instability is a characteristic of a majority of human malignancies. Chromosomal instability is a common form of genomic instability that can be caused by defects in mitotic checkpoint genes. Chromosomal aberrations in peripheral blood are also indicative of genotoxic exposure and potential cancer risk. We evaluated associations between inherited genetic variants in 33 mitotic checkpoint genes and the frequency of chromosomal aberrations (CAs) in the presence and absence of environmental genotoxic exposure. Associations with both chromosome and chromatid type of aberrations were evaluated in two cohorts of healthy individuals, namely an exposed and a reference group consisting of 607 and 866 individuals, respectively. Binary logistic and linear regression analyses were performed for the association studies. Bonferroni-corrected significant p-value was 5 × 10-4 for 99 tests based on the number of analyzed genes and phenotypes. In the reference group the most prominent associations were found with variants in CCNB1, a master regulator of mitosis, and in genes involved in kinetochore function, including CENPH and TEX14, whereas in the exposed group the main association was found with variants in TTK, also an important gene in kinetochore function. How the identified variants may affect the fidelity of mitotic checkpoint remains to be investigated, however, the present study suggests that genetic variation may partly explain interindividual variation in the formation of CAs.

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