Carcinogenesis Advance Access published online on August 13, 2008
Carcinogenesis, doi:10.1093/carcin/bgn193
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Polygenic Model of DNA-Repair Genetic Polymorphisms in Human Breast Cancer Risk
1 Sylvester Comprehensive Cancer Center
2 Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida
3 Department of Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina
4 Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
5 Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
* To whom correspondence should be addressed at: 1120 NW 14th Street, CRB Building #1511, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136. 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 4 DNA-repair pathways: (1) Base Excision Repair (BER): ADPRT V762A, APE1 D148E, XRCC1 R194W/R280H/R399Q, and POLD1 R119H; (2) Nucleotide Excision Repair (NER): ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H, and XPC A499V/K939Q; (3) Mismatch Repair (MMR): MLH1 I219V, MSH3 R940Q/T1036A, and MSH6 G39E; and (4) Double-Strand Break Repair (DSBR): 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.
Received April 7, 2008; revised July 28, 2008; accepted August 8, 2008.
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