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Carcinogenesis Advance Access originally published online on August 13, 2008
Carcinogenesis 2008 29(11):2132-2138; doi:10.1093/carcin/bgn193
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk

Tasha R. Smith1,2, Edward A. Levine3, Rita I. Freimanis4, Steven A. Akman5, Glenn O. Allen1, Kimberly N. Hoang1, Wen Liu-Mares1,2 and Jennifer J. Hu1,2,*

1 Sylvester Comprehensive Cancer Center
2 Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, 1120 NW 14th Street, CRB Building #1511, Miami, FL, USA
3 Department of Surgery
4 Department of Radiology
5 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA

* To whom correspondence should be addressed. Tel: +1 305 243 7796; Fax: +1 305 243 2997; Email: jhu{at}med.miami.edu

Genetic variations in DNA repair may impact repair functions, DNA damage and breast cancer risk. Using data/samples collected from the first 752 Caucasians and 141 African-Americans in an ongoing case–control study, we examined the association between breast cancer risk and 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways—(i) base excision repair: ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q and POLD1 R119H; (ii) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) double-strand break repair: NBS1 E185Q and XRCC3 T241M. In Caucasians, breast cancer risk was significantly associated with ADPRT 762VV [odds ratio (OR) = 1.45; 95% confidence interval (CI) = 1.03, 2.03], APE1 148DD (OR = 1.44; 95% CI = 1.03, 2.00), MLH1 219II/IV (OR = 1.87; 95% CI = 1.11, 3.16) and ERCC4 415QQ (OR = 8.64; 95% CI = 1.04, 72.02) genotypes. With a limited sample size, we did not observe any significant association in African-Americans. However, there were significant trends in breast cancer risk with increasing numbers of risk genotypes for ADPRT 762VV, APE1 148DD, ERCC4 415RQ/QQ and MLH1 219II/IV (Ptrend < 0.001) in Caucasians and ADPRT 762VA, ERCC2 751KQ/QQ and NBS1 185EQ/QQ in African-Americans (Ptrend = 0.006), respectively. Our results suggest that combined nsSNPs in multiple DNA repair pathways may contribute to breast cancer risk and larger studies are warranted to further evaluate polygenic models of DNA repair in breast cancer risk.

Abbreviations: BER, base excision repair; BMI, body mass index; CI, confidence interval; DSBR, double-strand break repair; FDR, false discovery rate; FH, family history; HR, homologous recombination; HWE, Hardy–Weinberg equilibrium; MARS, multivariate adaptive regression splines; MMR, mismatch repair; NER, nucleotide excision repair; nsSNP, non-synonymous single-nucleotide polymorphism; OR, odds ratio; SNP, single-nucleotide polymorphism

Received April 7, 2008; revised July 28, 2008; accepted August 8, 2008.


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