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XRCC3 Genetic Polymorphism, Smoking, and
Lung Carcinoma Risk in Minority Populations
March 22, 2004

Reviewed by:

Sharleen Traynor
MPH Candidate
Rollins School of Public Health
Department of Epidemiology
Emory University

The Health Outcome

Lung cancer is the leading cause of cancer deaths in both men and women in the United States . In the year 2003, it was predicted that 171,900 new cases of lung cancer cases would be diagnosed, and 157,200 people would die from the disease. There are two types of lung cancer-small cell lung cancer and non-small cell lung cancer. The more common type is non-small cell lung cancer, accounting for about 80% of lung cancers. It is generally slow-spreading, and includes three subtypes of disease, which are squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Small cell cancer is the more aggressive form of the disease. It grows rapidly and is likely to spread to other organs of the body (1).

The main cause of lung cancer is tobacco smoking. Almost 90% of lung cancer cases can be attributed to smoking. Other causes of lung cancer include exposure to radon, work-related chemicals, and other carcinogens found in the environment. Another hypothesis that is being explored is the relationship of lung cancer to reduced capacity for repair of damaged DNA.

There are several genes involved in the repair of DNA. One such gene is XRCC3 (X-Ray Cross-Complementing Group 3 gene) which has been shown to play a role in homology-directed repair of double-stranded DNA breaks. Although the specific function of this gene is still unclear, it is known to be associated with the RAD family of genes, and its gene products are believed to interact directly with RAD51 (2) . Disruption of this function may be caused by genetic polymorphisms, particularly the Thr241Met polymorphism on exon 7, which is caused by a single C to T substitution. It is believed that this disruption of XRCC3 function can hinder DNA repair and cause the accumulation of DNA damage, ultimately leading to genomic instability and increased cancer risk.

The Finding

Wang, et al conducted a hospital-based case-control study in three greater metropolitan areas in Texas . The purpose was to test the association of the XRCC3 Thr241Met (C to T) polymorphism, smoking, and lung cancer in African American and Mexican American populations. The 112 cases were newly diagnosed and histologically confirmed cases from various county, community, and VA hospitals. 190 controls were selected from community centers in the same geographic regions, and matched to cases by age, gender, ethnicity, and location of residence.

Blood samples were drawn from each participant to determine their XRCC3 genotype. The researchers found no significant difference in genotype frequencies between the two ethnic groups: the polymorphism appeared in about 22% of the subjects in both groups. Because of this similarity, the two groups were combined and treated as a single study group for subsequent analyses. The authors also observed that there was no overall association between the polymorphism and lung cancer (OR=1.25, 95% CI 0.72-2.15).

The authors were also interested in assessing the effect of smoking status on the gene-disease relationship, and information about smoking exposures was collected in a personal interview. Smokers were divided into two groups based on average amount smoked. Participants who smoked 0-30 pack-years were classified as "light smokers," and those who smoked > 30 pack-years were considered "heavy smokers." The analysis showed that there was a significant association between the XRCC3 polymorphism and lung cancer in heavy smokers (OR=37.31, 95% CI 11.43-121.72), but not in light smokers (OR=0.59, 95% CI 0.26-1.34). This indicates that polymorphism may modify the effect of smoking and its association with an increased risk of lung cancer.

Public Health Implications

The findings of this study indicate that heavy smokers with the XRCC3 polymorphism may be at an even larger risk of lung cancer than other smokers. More research needs to be done in this area to further explore the true role of this polymorphism in the development of cancer, as studies that have already been conducted have conflicting results (3). Such research may be useful in explaining and understanding the biological mechanisms of disease development. This information, however, does little to change public health efforts for this disease. Since such a large proportion of lung cancer cases is caused by smoking, cessation/prevention of tobacco smoking is the most effective tool for lung cancer prevention, regardless of XRCC3 genotype.

References

  1. American Lung Association. Lung Disease Data 2003.
  2. Matullo G et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking, and P-DNA adducts in a sample of health subjects. Carcinogenesis . 2001; 22(9): 1437-1445.
  3. David-Beabes G, et al. No association between the XPD (Lys751Gln) polymorphism or the XRCC3 (Thr241Met) polymorphism and lung cancer risk. Cancer Epidemiology, Biomarkers, and Prevention. 2001 August; 92: 562-567.
Last Updated August 14, 2004