Genetic Polymorphisms in the Base Excision Repair Pathway and Cancer Risk: A HuGE Review

• Published in: American journal of epidemiology Vol. 162; no. 10; pp. 925 - 942
• Main Authors: Hung, Rayjean J., Hall, Janet, Brennan, Paul, Boffetta, Paolo
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 15.11.2005; Oxford Publishing Limited (England)
• Subjects: 8-oxoguanine DNA glycosylase; Analysis. Health state; APE1/APEX1; apurinic/apyrimidinic endonuclease; Biological and medical sciences; Cancer; confidence interval; Confidence Intervals; Continental Population Groups - genetics; Continental Population Groups - statistics & numerical data; Database of Single Nucleotide Polymorphisms; dbSNP; Deoxyribonucleic acid; DNA; DNA Glycosylases - genetics; DNA repair; DNA Repair - genetics; DNA, Neoplasm - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-Binding Proteins - genetics; Epidemiology; Gene Frequency - genetics; General aspects; Genes; genetic; Genetic diversity; Global Health; Health risks; human; Humans; Lung cancer; Lung Neoplasms - epidemiology; Lung Neoplasms - genetics; Medical sciences; Meta-analysis; neoplasms; Neoplasms - epidemiology; Neoplasms - genetics; Odds Ratio; OGG1; Polymorphism; Polymorphism, Genetic - genetics; Prevalence; Public health. Hygiene; Public health. Hygiene-occupational medicine; Risk assessment; Risk reduction; Smoking - epidemiology; Smoking - genetics; Tobacco; X-ray Repair Cross Complementing Protein 1; x-ray repair cross-complementing group 1; XRCC1; XRCC1 protein; Human; genetic; XRCC1 protein; human; polymorphism; Review; Malignant tumor; Epidemiology; Metaanalysis; Health and environment; apurinic/apyrimidinic endonuclease; DNA repair; meta-analysis; neoplasms; 8-oxoguanine DNA glycosylase; DNA; Risk factor; Genetics; Repair; Bibliographic review; Polymorphism
• ISSN: 0002-9262; 1476-6256
• DOI: 10.1093/aje/kwi318

Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to cancer risk. However, epidemiologic findings have been inconsistent. The authors conducted meta-analyses of associations between genes in the base excision repair pathway and cancer risk, focusing on three key genes: 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease (APE1/APEX1), and x-ray repair cross-complementing group 1 (XRCC1). They found increased lung cancer risk among subjects carrying the OGG1 Cys/Cys genotype (odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.01, 1.53), using 3,253 cases and 3,371 controls from seven studies; this is consistent with experimental evidence that this isoform exhibits decreased activity. They found a protective effect of the XRCC1 194Trp allele for tobacco-related cancers (OR = 0.86, 95% CI: 0.77, 0.95), using 4,895 cases and 5,977 controls from 16 studies; this is compatible with evidence of lower mutagen sensitivity for this allele. The XRCC1 399Gln/399Gln genotype was associated with increased risk of tobacco-related cancers among light smokers (OR = 1.38, 95% CI: 0.99, 1.94) but decreased risk among heavy smokers (OR = 0.71, 95% CI: 0.51, 0.99), suggesting effect modification by tobacco smoking. There was no association between cancer risk and the APE1/APEX1 Asp148Glu and XRCC1 Arg280His polymorphisms. Recommendations for future studies include pooling of individual data to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental exposure.