Genetic polymorphisms of multiple DNA repair pathways impact age at diagnosis and TP53 mutations in breast cancer.

Defective DNA repair may contribute to early age and late stage at time of diagnosis and mutations in critical tumor suppressor genes, such as TP53 in breast cancer. Using DNA samples from 436 breast cancer cases (374 Caucasians and 62 African-Americans), we tested these associations with 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) double-strand break repair: NBS1 E185Q and XRCC3 T241M; (iii) mismatch repair: MLH1 I219V, MSH3 R940Q/T1036A and MSH6 G39E and (iv) nucleotide excision repair: ERCC2 D312N/K751Q, ERCC4 R415Q, ERCC5 D1104H and XPC A499V/K939Q. Younger age at diagnosis (<50) was associated with ERCC2 312 DN/NN genotypes [odds ratio (OR) = 1.

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

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.

DNA-repair genetic polymorphisms and breast cancer risk.

Mammalian cells are constantly exposed to genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair contributes to deficient repair and breast cancer risk. Using samples collected in an ongoing, clinic-based, case-control study (253 cases and 268 controls), we tested whether breast cancer risk is associated with four amino acid substitution variants in three DNA repair genes, including XRCC1 Arg194Trp and XRCC1 Arg399Gln in base excision repair, XRCC3 Thr241Met in homologous recombination repair, and ERCC4/XPF Arg415Gln in nucleotide excision repair.

DNA damage and breast cancer risk.

To evaluate whether deficient DNA repair contributes to elevated DNA damage and breast carcinogenesis, we used the comet assay (single-cell alkaline gel electrophoresis) to measure the levels of DNA damage in peripheral lymphocytes from 70 breast cancer cases and 70 controls. DNA damage, measured as the comet tail moment, was not influenced by age, family history (FH), age at menarche, age at first birth or parity. The results showed that cancer cases had significantly higher DNA damage compared with controls; the comet tail moments (mean +/- SD) for cases and controls were: 10.

Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer.

Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair may contribute to human cancer risk. We used a case-control study design (162 cases and 302 controls) to test the association between three amino acid substitution variants of DNA repair genes (XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 Thr241Met) and breast cancer susceptibility.

Genetic regulation of ionizing radiation sensitivity and breast cancer risk.

Genetic variability in DNA repair may contribute to hypersensitivity to ionizing radiation (IR) and susceptibility to breast cancer. We used samples collected from a clinic-based breast cancer case-control study to test the working hypothesis that amino acid substitution variants of DNA repair genes may contribute to prolonged cell-cycle delay following IR and breast cancer risk. Fluorescence-activated cell sorter (FACS) analysis was used to measure cell-cycle delay.