Genetic Profiling of Lung Cancer. V. Venkatraj¹, T. Bhari¹, G. Zhou², E.T. Castiglioni¹, J.C. Huber², P.W. Dunne¹, K.C. Donnelly². 1) Dept VIBS, Texas A&M Univ, College Station, TX; 2) SRPH,Texas A&M Univ, College Station, TX.
   Lung cancer is the leading cause of cancer mortality worldwide.DNA adducts formed as a consequence of exposure to tobacco smoke may be involved in carcinogenesis, and their quantification is used as a dosimeter to evaluate DNA repair and risk of lung cancer.In an effort to uncover the relationship between genetic changes and DNA repair we did a pilot study on primary lung tumors using two approaches. To determine the genomic copy changes in primary lung cancer evolution we employed array Comparative Genomic Hybridization (aCGH) technique (Spectral Chip TM 2600, Spectral Genomics,USA) on 10 lung primary tumors and normal tissue from adjoining areas. Second, to quantify DNA adducts we used nuclease-P1 enhanced 32P DNA post-labeling on these same samples. Our results indicated the average number of genetic aberrations were higher in smokers with lung cancer (20/tumor) compared to nonsmokers (13/tumor) with lung cancer. In addition, our data points to recurrent changes in several chromosomal regains; DNA gain of 1p13-21, 1p31-p36, 1q21-25, 8q12-24(60%) of the samples, followed by DNA gain of 1q42-43, 12q12-q24 (50%).DNA loss was observed less frequently and included 10q (40%) and 3p, 4q, 6q, 12p and 12q (30%). Some of the genes relevant to lung cancer tumoriginesis mapping to these loci include N-ras, GSTM1, L-Myc,EGFR-1,C-Myc,MDM2, Bcl-2, BAX, GSTT1,FHIT, PTEN, RARB,p16,RB and p27/Kip1. The Diagonal Radioactive Zone (DRZ) in the adjacent lung tissues from current smokers was higher than those from former smokers. Moreover, the number of DNA adducts was about 6 fold less in tumor tissue as when compared to adjoining normal tissue. These results support the conclusions that lung tumor cells in smokers have a higher frequency of chromosomal aberrations compared to lung tumor cells in nonsmokers, indicating an enhanced genomic instability. Furthermore our data points to the importance of analyzing the apparently normal adjoining tissue for genetic changes as they may reveal chromosomal changes that are relevant to early transformation events during lung cancer evolution and provide accurate quantification of DNA adducts compared to tumor samples.