Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering

To identify the major tumor suppressor gene (TSG) loci involved in the path ogenesis of lung cancer, we have conducted a high-resolution (10 cM), genom e-wide search of loss of heterozygosity (LOH). Thirty-six lung cancer cell lines [14 small cell lung cancers (SCLCs) and 22 non-SCLCs (NSCLCs)] and th eir matched control DNAs were analyzed using 399 fluorescent microsatellite markers from the ABI Prism linkage mapping set v.2 on an ABI 377 sequencer /genotyper. Overall, 22 different regions with more than 60% LOH were ident ified: (a) 13 regions with a preference for SCLC; (b) 7 regions with a pref erence for NSCLC; and (c) 2 regions affecting both SCLC and NSCLC. The chro mosomal arms with the most frequent LOH were 1p, 3p, 4p, 4q, 5q, 8p, 9p (p1 6), 9q, 10p, 10q, 13q (Rb), 15q, 17q (p53), 18q, 19p, Xp, Xq. In addition, new homozygous deletions were found at 2p23, 8q24, 18q11, and Xq22. On aver age, 34% (SCLC) to 36% (NSCLC) of markers showed allele Loss in individual tumors, with an average size of subchromosomal region of loss of five to si x markers (50-60 cM). Whereas SCLC and NSCLC had different regions of frequ ent LOH (hot spots), and NSCLC had more of these regions (n = 22) than SCLC (n = 17), in all other parameters (fractional allelic loss. number of brea kpoints, and number of microsatellite alterations), SCLC and NSCLC were not significantly different. Clustering analysis revealed correlations between LOH on different chromosomes that suggest previously unknown genetic inter actions fur lung cancer development. We conclude that (a) in lung cancer ce ll lines, at least 17-22 chromosomal regions with frequent allele loss are involved, suggesting that the same number of putative TSGs are inactivated; (b) SCLC and NSCLC frequently undergo different specific genetic alteratio ns; and (c) clusters of TSGs are Likely to be inactivated together. Overall , these data provide global estimates of the extent of genetic changes lead ing to lung cancer and will be useful fur the positional cloning of new TSG s and for the identification of multiple new biomarkers for translational r esearch.