DNA repair phenotype and cancer risk: a systematic review and meta-analysis of 55 case–control studies (original) (raw)

DNA repair phenotype can be measured in blood and may be a potential biomarker of cancer risk. We conducted a systematic review and meta-analysis of epidemiological studies of DNA repair phenotype and cancer through March 2021. We used random-effects models to calculate pooled odds ratios (ORs) of cancer risk for those with the lowest DNA repair capacity compared with those with the highest capacity. We included 55 case-control studies that evaluated 12 different cancers using 10 different DNA repair assays. The pooled OR of cancer risk (all cancer types combined) was 2.92 (95% Confidence Interval (CI) 2.49, 3.43) for the lowest DNA repair. Lower DNA repair was associated with all studied cancer types, and pooled ORs (95% CI) ranged from 2.02 (1.43, 2.85) for skin cancer to 7.60 (3.26, 17.72) for liver cancer. All assays, except the homologous recombination repair assay, showed statistically significant associations with cancer. The effect size ranged from 1.90 (1.00, 3.60) for the etoposide-induced double-strand break assay to 5.06 (3.67, 6.99) for the γ-H2AX assay. The consistency and strength of the associations support the use of these phenotypic biomarkers; however large-scale prospective studies will be important for understanding their use related to age and screening initiation. Cancer initiation is classically associated with the induction of mutations in key oncogenes or tumor suppressor genes, due to the presence of unrepaired/misrepaired DNA lesions produced by endogenous or exogenous genotoxic agents 1. Many risk factors for cancer such as smoking, ionizing radiation, and diet can induce DNA damage 2. Higher levels of DNA/protein adducts in blood from exogenous exposures are associated with increased cancer risk 3. DNA repair plays a fundamental role in the maintenance of genomic integrity 4. Individuals with deficiency in DNA repair capacity might be more susceptible to cancer risk. DNA repair capacity can be assessed either with genomic/proteomic approaches or with phenotypic approaches 5. A concern with genomic/proteomic approaches is that mammalian DNA damage repair mechanisms are extraordinarily complex. In humans it involves ~ 450 genes in 13 different pathways including 7 core and 6 associated pathways, with over half the proteins interacting with other proteins from different pathways (Fig. 1) 6 ; it follows that any specific genomic or proteomic methodology is unlikely to reflect overall DNA repair capacity. If it were possible to characterize the genetic complexity, it would be extremely challenging to implement at a clinical level. By contrast, phenotypic approaches-e.g., inducing DNA damage and then measuring the rate of DNA repair or the amount of unrepaired DNA damage, or both-have the potential to be more reflective of overall DNA repair capacity 7. DNA repair phenotyping assays use fresh or cryopreserved peripheral blood mononuclear cells (PBMC) or lymphoblastoid cell lines as a surrogates for target tissue of DNA repair 7. A phenotypic assay, if it is high throughput, may be more feasible to implement in a clinical setting as phenotypic approaches can reflect the totality of multiple complex pathways. The purpose of our systematic review and meta-analysis is to quantitatively and qualitatively summarize the literature regarding DNA repair phenotype and risk of cancer. We assessed the association of DNA repair