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Effects of Three DNA Repair Gene Polymorphisms on Bladder Cancer Risk

May 6, 2004
Abstraction Template
     
Key variables & Description Article

Reference
Complete the bibliographic reference for the article according to AJE format.

 

Shen, M, et al. Polymorphisms of the DNA Repair Genes XRCC1, XRCC3, XPD, Interaction with Environmental Exposures, and Bladder Cancer Risk in a Case- Control Study in Northern Italy . Caner Epidemiology, Biomarkers and Prevention. 2003 November;12:1234-1240.

 

Category of HuGE information
Specify the types of information (from the list below) available in the article:

  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 
  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction

Study hypotheses or purpose
The authors study hypotheses or main purpose for
conducting the study

 

 An association exists between three genetic polymorphisms in DNA repair genes [XRCC1 (Arg 399Gln), XRCC3 (Thr 241Met), and XPD (Lys 751 Gln)] and bladder cancer risk.

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #
  1. Gene name: XRCC1
  2. Chromosome location: 19q13.2-13.3
  3. Gene product/function: XRCC1 protein—“scaffolding protein” that fixes base damage and DNA single strand breaks; stimulates DNA kinase and DNA phosphatase, accelerating repair
  4. Alleles: Arg 399Gln, Arg 194Trp, Arg 280His
  5. OMIM #: 194360
  1. Gene name: XRCC3
  2. Chromosome location: 14q32.3
  3. Gene product/function: homologous recombination repair of DNA double strand breaks and cross- links; interacts directly with Rad51 (a eukaryotic homolog of the bacterial RecA recombinase)
  4. Alleles: Thr 241Met, IVS5 A-G
  5. OMIM #: 600675
  1. Gene name: XPD
  2. Chromosome location: 19q13.2-13.3
  3. Gene product/function: normal transcription initiation and nucleotide excision repair
  4. Alleles: Lys 751Gln
  5. OMIM #: 278730

 

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

 
  1. tobacco smoking
  2. occupational exposure to polycyclic aromatic hydrocarbons (PAHs)
  3. occupational exposure to aromatic amines

 

Health outcome(s)
Identification of the major health outcome(s) studied

 
  1. Bladder cancer
Study design
Specification of the type of study design(s)
  1. Case-control
  2. Cohort 
  3. Cross-sectional
  4. Descriptive or case series
  5. Clinical trial
  6. Population screening

 
  1. Hospital- based, case-control study
Case definition
For study designs 1, 4, and 5, define the following if available:
  1. Disease case definition
  2. Exclusion criteria
  3. Gender
  4. Race/ethnicity
  5. Age
  6. Time period
  7. Geographic location
  8. Number of participants (% of total eligible)

 
  1. Disease case definition: histologically- confirmed bladder cancer
  2. Exclusion criteria: female, refusal of interview or blood test
  3. Gender: male
  4. Race/ethnicity: Caucasians of Italian nationality
  5. Age: 20-80 years
  6. Time period: July 1997- December 2000
  7. Geographic location: Brescia province, northern Italy
  8. Number of participants: 201
Control definition
For study design 1, define the following if available:
  1. Control selection criteria
  2. Matching variables
  3. Exclusion criteria
  4. Gender
  5. Race/ethnicity
  6. Age
  7. Time period
  8. Geographic location
  9. Number of participants (% of total eligible)

 
  1. Control selection criteria: men admitted to urology departments of same hospitals and diagnosed with nonneoplastic urologic diseases (including: hydronephrosis, urolithiasis, malformative urological diseases, prostatic adenomas and hypertrophia, urological traumas, orchiepididymitis, hydrocele, unspecified urinary symptoms)
  2. Matching variables: age (+/- 5 years), period of recruitment, hospital of admission
  3. Exclusion criteria: female, refusal of interview or blood test
  4. Gender: male
  5. Race/ethnicity: Caucasians of Italian nationality
  6. Age: 20- 80 years Time period: July 1997- December 2000
  7. Geographic location: Brescia province, northern Italy
  8. Number of participants: 214

 
Assessment of environment factors
For studies that include gene-environment interactions, define the following, if available:
  1. Environmental factor
  2. Exposure assessment
  3. Exposure definition
  4. Number of participants with exposure data (% of total eligible)
  1. Environmental factor: tobacco smoking
  2. Exposure assessment:
 
  • questionnaire that asked about tobacco smoking and “leisure- time activity entailing chemical exposures”
  • three interviewers “experienced in occupational medicine” and aware of case/ control status
  3. Exposure definition:
 
  • cumulative lifetime smoking measured in pack- years
  • light and heavy, with cutoff of 26 (median pack- year for controls)[not very light!]
  4. Number of participants with exposure data: 415 (100%)
  1. Environmental factor: occupational exposure to PAHs and aromatic amines
  2. Exposure assessment: questionnaire that asked about occupational history and environmental PAH/chemical exposure was further assessed by an expert in occupational medicine and industrial hygiene who was blind to case/ control status
  3. Exposure definition: 1) absent, possible, probable, or definite 2) if exposure present, classified level, frequency and mode (respiratory or dermal) 3) for analysis, occupational exposure to PAHs and aromatic amines classified as never or ever exposed
  4. Number of participants with exposure data: 415 (100%)

 
Genotyping
Specify the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible) 
  1. Gene: XRCC1
  2. DNA source: white blood cells
  3. Methodology:
    • RFLP patterns obtained from literature and tested on subjects with known genotype
    • samples from study population underwent PCR followed by enzymatic digestion analysis
    • all uncertain results were reanalyzed
    • all analyses done in one laboratory by technicians blind to case/ control status
  4. Number of participants genotyped: 415 (100%)
  1. Gene: XRCC3
  2. DNA source: same as above
  3. Methodology: same as above
  4. Number of participants genotyped: 415 (100%)
  1. Gene: XPD
  2. DNA source: same as above
  3. Methodology: same as above
  4. Number of participants genotyped: 415 (100%)

 
Results
Describe the major results under each of the following HuGE categories. Include tables when data are provided:
  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring
  1. Prevalence of gene variant (Tables 1-3):
    • XRCC1 : cases 53.7%, controls 57.0%
    • XRCC3 : cases 55.7%, controls 66.8%
    • XPD : cases 60.7%, controls 62.6%

  2. Gene-disease association:
    • no significant association between XRCC1 codon 399 and bladder cancer or between XPD codon 751 and bladder cancer
    • variant carriers of XRCC3codon 241 showed significantly reduced risk of bladder cancer (OR 0.63, 95% CI 0.42- 0.93)

  3. Gene-environment interaction (Tables 4-5):
    • Smoking—
      i ) XRCC1 codon 399 variant showed a nonsignificant protective effect among heavy smokers, especially for the homozygous variant (OR 0.38, 95% CI 0.14- 1.02)
      ii) XRCC3 codon 241 variant showed a significantly reduced risk of bladder cancer only among heavy smokers (OR 0.49, 95% CI 0.28- 0.88)
      iii) XPD codon 751 was not a risk factor
      iv) no apparent multiplicative interaction between the three polymorphisms and smoking
    • PAHs: no evidence any of the three polymorphisms modified the effect of PAHs on bladder cancer
    • Aromatic amines: common XRCC1 and common XRCC3 carriers showed a nonsignificant increased risk of bladder cancer
Conclusion
State the author's overall conclusions from the study

The authors concluded that:

  • The XRCC3 codon 241 polymorphism had a protective effect against bladder cancer that was strongest among heavy smokers.
  • The XRCC1 codon 399 polymorphism had a nonsignificant protective effect against bladder cancer among heavy smokers.
The XPD polymorphism was not associated with bladder cancer risk.

 
Comments
Provide additional insight, including methodologic issues and/or concerns about the study

Biased selection of subjects

  • Control subjects had other non- neoplastic urologic diseases. The possibility that an association may exist between the studied polymorphisms and the diseases of controls was acknowledged by the authors, but not explored. The authors also admitted that there may exist different referral patterns for patients with bladder cancer vs. those with other urological conditions which may lead to selection bias.
  • There was no mention of physical examinations or laboratory data other than genotype. It was not clear whether control subjects had undergone evaluations to rule out bladder cancer (eg, urinalysis, urine cytology, cystoscopic examination).

Exposure misclassification

  • The three interviewers had knowledge of case/ control status of participants which may have affected the validity and reproducibility of the exposure assessment, and therefore biased the estimation of interaction effect.
  • The questionnaire was described as “semi-structured”, which may also have affected the validity and reproducibility of the exposure assessment.
  • The categorization of smoking results was not clear. Some results presented included ex- smokers which were not mentioned in the statistical methods section.

Finally, it is not possible to draw inferences about the frequencies of these polymorphisms or their interactions with smoking and bladder cancer in women, because women were not included in this study.

 
Last Updated August 25, 2004