Breast Cancer Risk Associated with Genotypic Polymorphism of Oxidative DNA Damage Repair Genes - A Multigenic Study of Base Excision Repair and Transcription-Coupled Repair in Cancer Susceptibility

Chiun-Sheng Huang ； Jia-Jiu Chen ； Shi-Yi Yang ； Chun-Wen Cheng ； Herng-Der Chern ； King-Jen Chang ； Pei-Ei Wu ； Chen-Yang Shen

《Journal of Genetics and Molecular Biology》 15卷2期 (2004/06) Pp. 116-136

https://doi.org/10.30047/JGMB.200406.0006

並列摘要

Estrogen is suggested to play a dual role in breast cancer development, both as a promoter, triggering cell proliferation, and as an initiator, causing the DNA damage essential for driving tumorigenesis. The initiator mechanism of estrogen is suggested to involve its metabolite, catechol estrogen, which has been shown to lead to oxidative DNA damage in vitro. To test this possibility in human breast cancer, a multigenic case-control study was conducted to determine whether the association between estrogen exposure and breast cancer risk might be modified by genotypic polymorphism of the genes involved in oxidative damage repair, including those involved in base excision repair (BER)(hOGG1, APE1, and XRCC1) and transcription-coupled repair (TCR)(XPD and BRCA1). One hundred and thirty-six breast cancer patients and 232 healthy controls were recruited and the single-nucleotide polymorphisms (SNPs) and genotypes of their oxidative damage repair genes determined by PCR-based RFLP assays. Women with low-risk genotypes of repair genes (hOGG1 codon326 Ser/Ser or Cys/Ser, APE1 codon148 Glu/Glu or Glu/Asp, XRCC1 codon399 Arg/Arg or Gln/Arg, XPD codon751 Lys/Lys, or BRCA1 codon871 Pro/Pro) showed no significant association between increased cancer risk and longer estrogen exposure (＞10 years) from menarche to first full-term pregnancy, whereas women with high-risk genotypes(hOGG1 codon326 Cys/Cys, APE1 codon148 Asp/Asp, XRCC1 codon399 Gln/Gln, XPD codon751 Gln/Lys or Gln/Gln, or BRCA1 codon871 Leu/Pro or Leu/Leu) showed a consistently stronger and significant association. Furthermore, a trend to an increased risk of developing breast cancer was found in women harboring higher numbers of high-risk genotypes of the BER and TCR genes (P=0.009), particularly in those with prolonged estrogen exposure. Interestingly, this study provided supporting evidence for an interaction, during breast tumorigenesis, between BER and TCR via BRCA1, by demonstrating both an extra independent risk (aOR, 2.1;95%CI, 1.1-4.0) of breast cancer in those women in whom both the BER and TCR pathways were defective and a more pronounced risk (aOR, 1.8; 95%CI, 1.1-3.1), associated with defective BER, in women with high-risk BRCA1 genotypes. On the basis of a comprehensive profile of DNA oxidative damage repair genes, this study has not only confirmed a carcinogenic mechanism by which estrogen causes DNA lesions, but has also shed light on a connection between TCR and BER in the prevention of oxidative damage and breast cancer development.

並列關鍵字

breast cancer ； breast cancer risk ； genotypic polymorphism ； oxidative DNA damage ； repair genes ； cancer susceptibility