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Homologous recombination repair capacity in peripheral blood lymphocytes and breast cancer risk.

ABSTRACT: Deficiency in homologous recombination repair (HRR) capacity is frequently observed in breast tumors. However, whether HRR deficiency is a tumor-specific biomarker or a risk factor for breast cancer is unknown. In this two-stage study, using a host cell reactivation assay, we assessed the relationship between HRR capacity in peripheral blood lymphocytes (PBLs) and breast cancer risk. The discovery stage included 152 breast cancer patients and 152 healthy controls matched on age and race. HRR capacity was found to be significantly lower in Black women than in White women among controls (P = 0.015) and cases (P = 0.012). Among cases, triple negative breast cancer patients had significantly lower HRR capacity than ER+/PR+ breast cancer patients (P = 0.006). In risk assessment, HRR capacity was found to be significantly lower in cases than in controls (P < 0.001), and decreased HRR capacity was associated with 1.42-fold increased risk of breast cancer (95% CI: 1.21, 2.53). In the validation stage, we assessed HRR capacity in a nested case-control study using pre-diagnostic samples. We found that decreased HRR capacity was associated with 1.21-fold increased risk of breast cancer (95% CI: 1.04, 4.58). In summary, our results demonstrate that decreased HRR capacity in PBLs is a risk factor for breast cancer.

SUBMITTER: Shen J

PROVIDER: S-EPMC7566366 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDNA repair capacity is an important determinant of susceptibility to cancer. The hOGG1 enzyme is crucial for repairing the 8-oxoguanine lesion that occurs either as a byproduct of oxidative metabolism or as a result of exogenous sources such as exposure to cigarette smoke. It has been previously reported that smokers with low hOGG1 activity had significantly higher risk of developing lung cancer as compared to smokers with high hOGG1 activity.MethodsIn the current study we elucidate the association between plasma levels of 8-OHdG and the OGG1 repair capacity. We used the commercially available 8-OHdG ELISA (enzyme-linked immunosorbent assay), the Comet assay/FLARE hOGG1 (Fragment Length Analysis by Repair Enzymes) assay for quantification of the levels of 8-OHdG and measured the constitutive, induced and unrepaired residual damage, respectively. We compared the DNA repair capacity in peripheral blood lymphocytes following H2O2 exposure in 30 lung cancer patients, 30 non-, 30 former and 30 current smoker controls matched by age and gender.ResultsOur results show that lung cancer cases and current smoker controls have similar levels of 8-OHdG lesions that are significantly higher compared to the non-smokers controls. However, lung cancer cases showed significantly poorer repair capacity compared to all controls tested, including the current smokers controls. After adjustment for age, gender and family history of smoking-related cancer using linear regression, we observed a 5-fold increase in risk of lung cancer associated with high levels of residual damage/reduced repair capacity. Reduced OGG1 activity could be expected to be a risk factor in other smoking-related cancers.ConclusionOur study shows that the Comet/FLARE assay is a relatively rapid and useful method for determination of DNA repair capacity. Using this assay we could identify individuals with high levels of residual damage and hence poor repair capacity who would be good candidates for intensive follow-up and screening.

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Homologous recombination repair capacity in peripheral blood lymphocytes and breast cancer risk.

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