ALTERATIONS OF K-RAS, P53, AND ERBB-2 NEU IN HUMAN LUNG ADENOCARCINOMA/

The development of human adenocarcinoma of the lung involves multiple genetic changes including activation of oncogenes and loss of tumor su ppressor genes. Patients whose lung tumors contain K-ras oncogene muta tion, accumulation of the protein product of the tumor suppressor gene p53, or erbB-2/neu oncoprotein overexpression have been shown to have a worse prognosis. We examined these three genetic indicators in 29 l ung adenocarcinomas to determine whether these markers are present in the same tumors or if they represent molecular changes that define dif ferent subsets of patients. P53 nuclear protein accumulation anti erbB -2/neu protein overexpression were determined by immunohistochemical a nalysis of cryostat sections of tumor specimens and corresponding norm al lung tissue. K-ras mutations were detected by radiolabeled oligonuc leotide probes, specific for the various twelfth codon mutations, hybr idized to exon 1 of K-ras, which was amplified by the polymerase chain reaction. Increased nuclear accumulation of p53 protein was found in 11 adenocarcinomas (38%). All of the p53 positive tumors were found to show high level staining and homogeneous expression of erbB-2/neu pro tein. K-ras mutations were detected in seven tumors (24%), all of whic h overexpressed erbB-2/neu. The presence of a K-ras mutation did not c orrelate with p53 accumulation. In total, 93% of the tumors were found to overexpress erbB-2/neu, the highest being in one tumor with erbB-2 /neu gene amplification. The presence of K-ras twelfth codon mutation was associated with increased cigarette smoking. In conclusion, erbB-2 /neu overexpression is a common event in lung adenocarcinomas. Further more, the presence of K-ras mutation and p53 protein accumulation defi ne separate groups of patients. The mechanisms by which these genetic alterations interact or adversely affect prognosis is unknown.