Interactions of DNA repair gene variants modulate chromosomal aberrations in healthy subjects.
Human cancers are often associated with numerical and structural chromosomal instability. Structural chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBL) arise as consequences of direct DNA damage or due to replication on a damaged DNA template. In both cases, DNA repair is critical and inter-individual differences in its capacity are probably due to corresponding genetic variations. We investigated functional variants in DNA repair genes (base and nucleotide excision repair, double-strand break repair) in relation to CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) in healthy individuals. Chromosomal damage was determined by conventional cytogenetic analysis. The genotyping was performed by both restriction fragment length polymorphism and TaqMan allelic discrimination assays. Multivariate logistic regression was applied for testing individual factors on CAs, CTAs and CSAs. Pair-wise genotype interactions of 11 genes were constructed for all possible pairs of single-nucleotide polymorphisms. Analysed individually, we observed significantly lower CTA frequencies in association with XPD Lys751Gln homozygous variant genotype [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.48-0.85, P = 0.004; n = 1777]. A significant association of heterozygous variant genotype in RAD54L with increased CSA frequency (OR 1.96, 95% CI 1.01-4.02, P = 0.03) was determined in 282 subjects with available genotype. By addressing gene-gene interactions, we discovered 14 interactions significantly modulating CAs, 9 CTAs and 12 CSAs frequencies. Highly significant interactions included always pairs from two different pathways. Although individual variants in genes encoding DNA repair proteins modulate CAs only modestly, several gene-gene interactions in DNA repair genes evinced either enhanced or decreased CA frequencies suggesting that CAs accumulation requires complex interplay between different DNA repair pathways.
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Institute of Biology and Medical Genetics, 1st Faculty of Medicine, Charles University in Prague, 12800 Prague, Czech Republic, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 32300 Pilsen, Czech Republic, pvodicka@biomed.cas.cz.
Pavel
P
Vodicka
Clinic of Occupational Medicine and Toxicology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava and University Hospital in Martin, 03601 Martin, Slovak Republic.
Ludovit
L
Musak
Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
Christoph
C
Frank
Faculty of Medicine, Slovak Medical University in Bratislava, 83303 Bratislava, Slovak Republic.
Alena
A
Kazimirova
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Institute of Biology and Medical Genetics, 1st Faculty of Medicine, Charles University in Prague, 12800 Prague, Czech Republic.
Veronika
V
Vymetalkova
Faculty of Medicine, Slovak Medical University in Bratislava, 83303 Bratislava, Slovak Republic.
Magdalena
M
Barancokova
Department of Cancer Genetics, Cancer Research Institute of Slovak Academy of Sciences, 83391 Bratislava, Slovak Republic.
Bozena
B
Smolkova
Molecular Biology Service, Research Institute for Molecular Pathology, 1030 Vienna, Austria.
Zuzana
Z
Dzupinkova
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Institute of Biology and Medical Genetics, 1st Faculty of Medicine, Charles University in Prague, 12800 Prague, Czech Republic.
Katerina
K
Jiraskova
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Institute of Biology and Medical Genetics, 1st Faculty of Medicine, Charles University in Prague, 12800 Prague, Czech Republic, Department of General Biology and Genetics, 3rd Faculty of Medicine, Charles University in Prague, 10000 Prague, Czech Republic.
Sona
S
Vodenkova
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.
Michal
M
Kroupa
Clinic of Occupational Medicine and Toxicology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava and University Hospital in Martin, 03601 Martin, Slovak Republic.
Oto
O
Osina
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Molecular and Genetic Epidemiology Research Unit, HuGeF-Human Genetics Foundation, 10126 Torino, Italy.
Alessio
A
Naccarati
Department of Agrobiology and Agrochemistry, University of Tuscia, 011000 Viterbo, Italy.
Fabrizio
F
Palitti
Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany, Center for Primary Health Care Research, Lund University, 20506 Malmö, Sweden and.
Asta
A
Försti
Health Effects Laboratory MILK, NILU-Norwegian Institute for Air Research, 2027 Kjeller, Norway.
Maria
M
Dusinska
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic, Institute of Biology and Medical Genetics, 1st Faculty of Medicine, Charles University in Prague, 12800 Prague, Czech Republic, Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 32300 Pilsen, Czech Republic.
Ludmila
L
Vodickova
Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany, Center for Primary Health Care Research, Lund University, 20506 Malmö, Sweden and.
Kari
K
Hemminki
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000076105:X-ray Repair Cross Complementing Protein 1; D055815:Young Adult
D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human