Multiple high-grade bronchial dysplasia and squamous cell carcinoma: Concordant and discordant mutations

Loss of heterozygosity (LOH) involving chromosomes 3p, 5q, 9p, or 17p and a berrant expression or mutation of p53 are reported previously in selected b ronchial dysplasias and squamous cell cancers (SCCs), Yet, comprehensive an alyses of LOH patterns at these chromosomal sites and of p53 alterations ar e not reported for histologically normal bronchial epithelium, high-grade b ronchial dysplasia, and SCC present in the same pulmonary resections, Wheth er concordant or discordant genetic changes are detected in these bronchial tissues, especially when multiple high-grade dysplastic bronchial lesions are present, was studied. Genomic DNA was microdissected from eight pulmona ry SCCs and high-grade dysplastic lesions that were associated with SCC, In four cases, two independent high-grade dysplastic bronchial lesions were i dentified, When available, histologically normal bronchial epithelium was m icrodissected, Germ-line genomic DNA was isolated from normal lymph nodes, LOH was assessed for 15 microsatellite markers on chromosomes 3p, 5q, 9p, o r 17p, sites frequently deleted in lung cancers. Immunohistochemical p53 ex pression was studied and correlated with p53 DNA sequence analyses. Progres sive LOH for these markers was found when SCCs were compared with high-grad e dysplasia and histologically normal bronchial epithelium present in the s ame resections, Histologically normal bronchial specimens had LOH in up to 27% of informative markers. High-grade dysplastic lesions exhibited LOH for 18-45% and SCC had LOH for 18 -73 % of the markers. Common regions of LOH were found in some dysplasias compared with SCCs, In other dysplasias, disc ordance was found relative to SCCs, especially for p53 mutations. In cases with a single or second high-grade dysplasia associated with SCC, heterogen eity in LOH markers was detected, These concordant and discordant changes w ere consistent with convergent and divergent clonal selection pathways in p ulmonary squamous cell carcinogenesis. Some histologically normal bronchial epithelial tissues had genetic changes more similar to those in the SCCs t han in dysplastic lesions. DNA loss or mutations accumulate in SCC, but dis cordant genetic changes can exist in the same carcinogen-exposed bronchial tissues, These findings have implications for lung cancer prevention trials .