Interactions of DNA repair gene variants modulate chromosomal aberrations in healthy subjects.
(2015) In Carcinogenesis 36(11). p.1299-1306- Abstract
- 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... (More)
- 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. (Less)
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https://lup.lub.lu.se/record/8042647
- author
- organization
- publishing date
- 2015
- type
- Contribution to journal
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- published
- subject
- in
- Carcinogenesis
- volume
- 36
- issue
- 11
- pages
- 1299 - 1306
- publisher
- Oxford University Press
- external identifiers
-
- pmid:26354780
- wos:000366386800006
- scopus:84976491936
- ISSN
- 0143-3334
- DOI
- 10.1093/carcin/bgv127
- language
- English
- LU publication?
- yes
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- d99a94a7-e048-4fe0-8157-ac64c892087d (old id 8042647)
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@article{d99a94a7-e048-4fe0-8157-ac64c892087d,
abstract = {{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.}},
author = {{Vodicka, Pavel and Musak, Ludovit and Frank, Christoph and Kazimirova, Alena and Vymetalkova, Veronika and Barancokova, Magdalena and Smolkova, Bozena and Dzupinkova, Zuzana and Jiraskova, Katerina and Vodenkova, Sona and Kroupa, Michal and Osina, Oto and Naccarati, Alessio and Palitti, Fabrizio and Försti, Asta and Dusinska, Maria and Vodickova, Ludmila and Hemminki, Kari}},
issn = {{0143-3334}},
language = {{eng}},
number = {{11}},
pages = {{1299--1306}},
publisher = {{Oxford University Press}},
series = {{Carcinogenesis}},
title = {{Interactions of DNA repair gene variants modulate chromosomal aberrations in healthy subjects.}},
url = {{http://dx.doi.org/10.1093/carcin/bgv127}},
doi = {{10.1093/carcin/bgv127}},
volume = {{36}},
year = {{2015}},
}