Synergistic effects of polymorphisms in DNA repair genes and endogenous estrogen exposure on female breast cancer risk.
BACKGROUND
Endogenous estrogen is suggested to initiate cell proliferation and cause oxidative DNA damage during breast tumorigenesis. Cells eliminate DNA damage by means of repair enzymes. Genotypic variants of DNA damage repair genes, participating in base excision repair (BER) and nucleotide excision repair (NER) pathways, may act as modifiers that affect the association between estrogen exposure and breast cancer.


METHODS
In a hospital-based case-control study of female breast cancer, DNA samples were obtained from 401 cases and 533 enrolled healthy controls, all of whom were Chinese women in Taiwan. Genotyping of polymorphisms of XRCC1 (Arg194Trp and Arg399Gln), OGG1 (Ser326Cys and Arg229Gln), ERCC2 Lys751Gln, ERCC4 Ser662Pro, and ERCC5 His1104Asp was performed and used to evaluate breast cancer susceptibility.


RESULTS
Of the nonsynonymous polymorphisms, the ERCC5 1104Asp variant was significantly associated with breast cancer (odds ratio = 1.42; 95% confidence interval = 1.08-1.97), and this association was more pronounced in women with lengthy estrogen exposure. A trend toward an increased risk of developing breast cancer was observed in women who carried greater numbers of combined high-risk genotypes of BER and NER genes (P(trend) = .038). The synergistic effect of multiple genes on the increase of risk was significant in women with a longer period of estrogen exposure (>26 years), greater age at first full-term pregnancy (>26 years), a longer menarche-to-first full-term pregnancy interval (>11 years), and higher body mass index (>22) (all P<.05).


CONCLUSIONS
This study demonstrates that genotype polymorphisms related to DNA damage repair confer greater susceptibility to endogenous estrogen in the development of breast cancer in women.
Ming-Shiean
Hsu
H
Division of General Surgery, Yuanli Lee's General Hospital, Lee's Medical Corporation, Miaoli, Taiwan.
Yu
Jyh-Cherng
JC
Wang
Hsiao-Wei
HW
Chen
Shou-Tung
ST
Hsiung
Chia-Ni
CN
Ding
Shian-ling
SL
Wu
Pei-Ei
PE
Shen
Chen-Yang
CY
Cheng
Chun-Wen
CW
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004357:Drug Synergism; D004720:Endonucleases / Q000235:genetics; D004967:Estrogens / Q000502:physiology*; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics; D000099250:DNA Excision Repair Protein ERCC-5
D045647:DNA Glycosylases; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004720:Endonucleases; D004967:Estrogens; D009687:Nuclear Proteins; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein; D000099250:DNA Excision Repair Protein ERCC-5; C000619371:XRCC1 protein, human; C095888:xeroderma pigmentosum group F protein; C479058:oxoguanine glycosylase 1, human; C497292:ERCC2 protein, human