Association of single nucleotide polymorphisms within DNA repair genes with bronchial premalignant lesions in heavy ex-smokers.

A38

Lung cancer develops as a result of complex interactions between genetic predisposition and environmental influences. Exposure to carcinogens such as tobacco smoke leads to DNA damage. Altered DNA repair capacity (DRC) combined with chronic, repetitive exposure to carcinogens may cause irreversible mutations and ultimately lead to the development of lung cancer. Little is known about the potential role of single nucleotide polymorphisms (SNPs) within DNA repair genes on the risk of lung pre-malignant lesions. We hypothesize that aberrant functional SNPs of genes involved in DNA repair may increase lung cancer susceptibility, contribute to lung carcinogenesis and is associated with presence of premalignant lesions in high-risk individuals. In an on-going lung cancer chemoprevention trial entitled, “Lung Cancer Chemoprevention with Celecoxib in EX-smokers (U01 CA96134, PI: J T Mao), high risk former smokers are being recruited and screened with spiral CT and fluorescence bronchoscopy for detection and monitoring of pre-malignant lesions. A variety of biological specimens, including buccal cells are being collected simultaneously from these subjects. To test our hypothesis, we utilized DNA isolated from buccal cells obtained from baseline screening and assayed functional SNPs of 29 genes in the DNA damage repair pathway. Using the ABI high-throughput SNPlex platform, 12 double strand break repair (DSBR) genes, 13 base excision repair (BER) genes, and 4 nucleotide excision repair (NER) genes have been evaluated. Based on preliminary analyses of SNPs in 89 participants, after adjusting for age, sex, race, education level, income, and pack-years of smoking, possible associations were suggested between presence of abnormal bronchial biopsy (squamous metaplasia and/or dysplasia) and the NBS1 of the DSBR pathway and ADPRT of the BER pathway, using a case-control study design (presence vs. absence of squamous metaplasia and/or dysplasia on bronchial biopsies). Our findings suggest that SNPs of DNA repair pathway may be useful in the identification of lung pre-malignant lesions and in the prediction of lung cancer risk.