title: APE1 genotype and risk of bladder cancer: evidence for effect modification by smoking.
abstract: Apurinic/apyrimidinic (AP) sites are common mutagenic and cytotoxic DNA lesions that arise from the loss of normal bases. APE1, the major AP endonuclease of human cells, plays a central role in the repair of AP sites through both its endonuclease and phosphodiesterase activities. A common APE1 polymorphism, a T-->G transversion (Asp 148 Glu), was previously shown to be associated with risk of lung cancer, an association that was modified by cigarette smoking. To explore the association between APE1 genotype, smoking and bladder cancer risk, we examined data from an existing case-control study of bladder cancer patients (n = 239) and control individuals (n = 215) recruited from urology clinics at 2 hospitals in North Carolina. Genotype at the polymorphic site was determined using allele-specific primer extension reactions, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We found no overall association between APE1 genotype and bladder cancer risk. In stratified analyses, however, a positive association with risk was observed with an increasing number of Glu alleles among never smokers, but not among smokers (p-value for interaction = 0.005). We can speculate that small allelic differences that are apparent in never smokers are obscured by the large amount of DNA damage found in smokers. Given the lack of established biological mechanisms, and suboptimal numbers of subjects in some exposure categories, our findings should be interpreted cautiously.
authors.affiliation: Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Terry
authors.forename: David M
authors.initials: DM
authors.lastname: Umbach
authors.forename: Jack A
authors.initials: JA
authors.lastname: Taylor
mesh_terms: D000368:Aged; D001224:Aspartic Acid; D016022:Case-Control Studies; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D005260:Female; D005838:Genotype; D018698:Glutamic Acid; D006147:Guanine; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D009657:North Carolina / Q000453:epidemiology; D011110:Polymorphism, Genetic; D018570:Risk Assessment; D012907:Smoking / Q000009:adverse effects*; D013941:Thymine; D001749:Urinary Bladder Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; D006147:Guanine; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D013941:Thymine