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

Paz-Elizur T, et al. DNA repair activity for oxidative damage and risk of lung cancer. Journal of the National Cancer Institute 2003 September;95(17):1312- 1319.

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

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

Study Purpose: The authors investigated whether the activity of the DNA repair enzyme OGG is associated with lung cancer.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: OGG1, 8- oxoguanine DNA glycosylase
2. Chromosome location: 3p26.2
3. Gene product/function: OGG1 encodes the glycosylase that removes the oxidative DNA lesion 8- oxoguanine.
4. Alleles: Ser326Cys
5. OMIM #: 601982

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

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

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

Case definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Case selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Disease case definition: Histopathologically confirmed operable non small cell lung cancer
2. Exclusion criteria: Prior chemotherapy or radiation therapy, previous smoking
3. Gender: Men and women
4. Race/ethnicity: Not specified
5. Age: 44-80
6. Time period: April 1999 through January 2002
7. Geographic location: Tel Hashomer , Israel
8. Number of participants: 68

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

1. Control selection criteria: Apparently healthy volunteers from participating medical center and science institute, including employees and their relatives and retired employees. A questionnaire was used to collect information on demographics and lung cancer risk factors.
2. Matching variables: Age and sex
3. Exclusion criteria: Prior cancer, previous smoking
4. Gender: Men and women
5. Race/ethnicity: Not specified
6. Age: 44- 78
7. Time period: April 1999 through January 2002
8. Geographic location: Rehovot and Tel Hashomer , Israel
9. Number of participants: 68

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
3. Exposure definition: Current smoker
4. Number of participants with exposure data: N (% of total eligible): 50.7%

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: OGG1
2. DNA source: protein extracts from peripheral blood mononuclear cells and lung tissue
3. Methodology: OGG1 activity assay: a synthesized oligonucleotide containing a site- specific 8-OH-G residue was incubated with the protein extracts from the PBMCs or lung samples. OGG activity was calculated by dividing the activity by the amount of protein in the reaction mixture. With respect to the samples of lung tissue, OGG was normalized to the total DNA amount rather than the total protein amount in an attempt to better represent the intracellular contents and discount the protein due to the abundant extracellular matrix.
4. Number of participants genotyped: none

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

2. Gene-disease association: see tables
3. Gene-environment interaction:

The authors concluded that low OGG activity is associated with an increased risk of lung cancer, and suggested that targeted smoking cessation in these patients might be an effective strategy in lung cancer prevention.

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

Biased selection of subjects

• The demographic information provided was limited to age and sex. No information was given concerning ethnicity, environment, or diet.
• All cases came from one medical facility, and all controls were either current or past employees of that or one other facility, or the relatives of those employees. There is no indication of the size of the geographic areas served by these facilities.
• Small cell lung cancer is also caused by smoking, yet patients with this disease were excluded from this study. Past studies have shown some relationship between OGG1 and small cell lung cancer (1,2). One may assume patients with small cell lung cancer were not included because they are usually not surgical candidates, so tissue procurement would prove more difficult.
• Only patients with operable NSCLC were included. This leaves open the possibility for selection of smaller, less aggressive cancers.
• Prior cancer is not part of the exclusion criteria for case patients.
• There was no information given about the length of time or quantity of smoking. As stated previously, these factors are known to impact lung cancer risk. It would also have been interesting to observe the effect of smoking cessation on OGG1 activity by including subjects who had smoked in the past (ever smokers), as smoking cessation is being advocated by the authors.

Confounding

Although the authors did recognize the possibility that OGG activity could be affected by tumor factors     secreted into the bloodstream, the results of their investigation into this matter do not appear to be conclusive. They evaluated OGG activity “from 4 months before surgery to more than 1 year after surgery”. This time frame is somewhat vague, and it is unclear how controls were used in this portion of the study.

Insufficient testing for assay validity

• There is no evidence of correlation between the assay developed by the authors and genotype.
• When a linear increase in DNA cleavage with increasing time of incubation and in relation to protein concentration within the reaction mixture was noted, the authors tested OGG activity from only 8 individuals over a three year period and found that the coefficient of variation averaged 7%. From this they concluded that OGG activity values from the same person are stable over a period of at least three years. It is not clear how or which 8 of the 136 participants were chosen for this sampling, and unmatched data are presented.
• With respect to the lung samples that were taken for the assay, how many patients’ lungs were sampled and why those particular patients were chosen is not clear. Also, no tissue was taken from lung involved with tumor, which would have been interesting for comparison.

When calculating linear regression to compare OGG activity in PBMCs (dependent variable) and that in lungs (independent variable) to determine whether OGG activity in PBMCs could substitute for OGG activity in the lungs, only 7 case patients were used.