Carcinogenesis Advance Access originally published online on June 19, 2008
Carcinogenesis 2008 29(7):1367-1372; doi:10.1093/carcin/bgn140
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Double-strand breaks repair in lymphoblastoid cell lines from sisters discordant for breast cancer from the New York site of the BCFR
Department of Environmental Health Sciences
1 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
To whom correspondence should be addressed. Tel: +1 212 305 8158; Fax: +1 212 305 5328; Email: rps1{at}columbia.edu
Unrepaired DNA double-strand breaks (DSBs) may have serious consequences for cells by inducing chromosomal aberrations, thereby increasing genetic instability and cancer risk. One's capacity to repair DSB is therefore an important factor to consider when estimating cancer risk. We assessed DNA end-joining (EJ) capacity in cell lines derived from sisters discordant for breast cancer to determine if individual differences in DSB repair are a significant risk factor. We used an in vitro phenotypic assay on nuclear extracts from lymphoblasts of 179 subjects including 86 cases and 93 controls. EJ activity was functionally estimated as the ability of extracts to join together monomers of the plasmid pUC18 linearized either with sticky (EcoRI) or blunt ends (HincII). Mean percentage of EJ capacity was slightly lower in cases than controls, both for EcoRI (cases 27.9 ± 11.1; controls 29.6 ± 10.7, P = 0.28) and HincII substrates (cases 28.8 ± 12.2; controls 30.6 ± 13.0, P = 0.36); however, no significant differences were observed. Categorizing EJ capacity into tertiles and using the highest activity as the referent, we observed elevated associations for each tertile of decreased repair [Odds ratio (OR) = 2.20, 95% confidence interval (CI) = 0.77–6.22 and OR = 4.22, 95% CI thinsp;= 1.22–14.0, P = 0.02], respectively, for EcoRI. Results were not statistically significant for HincII (OR = 1.37, 95% CI = 0.51–3.70 and OR = 2.32, 95% CI = 0.57–9.38, P = 0.24). These data suggest that individual differences in EJ capacity may represent a risk factor predisposing women to breast cancer.
Abbreviations: CI, confidence interval; DSB, double-strand break; EJ, end joining; HR, homologous recombination; NER, nucleotide excision repair; NHEJ, non-homologous end joining; OR, odds ratio; SNP, single-nucleotide polymorphism
Received January 24, 2008; revised June 4, 2008; accepted June 5, 2008.