Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion

The beta -catenin gene (CTNNB1) has been shown to be genetically mutated in various human malignancies. To determine whether the beta -catenin gene is responsible for oncogenesis in thoracic malignancies, we searched for the mutation in 166 lung cancers (90 primary tumors and 76 cell lines), one bla stoma and 10 malignant mesotheliomas (two primary tumors and eight cell lin es). Among the lung cancers, including 43 small cell lung cancers (SCLCs) a nd 123 non-small cell lung cancers (NSCLCs), we identified four alterations in exon 3, which is the target region of mutation for stabilizing beta -ca tenin. One primary adenocarcinoma had a somatic mutation from C to G, leadi ng to an amino acid substitution from Ser to Cys at codon 37. Among the cel l lines, SCLC NCI-H1092 had a mutation from A to G, leading to an Asp to Cr y substitution at codon 6, NSCLC HCC15 had a mutation from C to T, leading to a Ser to Phe substitution at codon 45, and NSCLC NCI-H358 had a mutation from A to G, leading to a Thr to Ala substitution at codon 75. One blastom a also had a somatic mutation from C to C, leading to a Ser to Cys substitu tion at codon 37. Among the 10 malignant mesotheliomas, we identified a hom ozygous deletion in the NCI-H28 cell line. Cloning of the rearranged fragme nt from NCI-H28 indicated that all the exons except exon 1 of the beta -cat enin gene are deleted and that the deletion junction is 13 kb downstream fr om exon 1. Furthermore, Northern blot analysis of 26 lung cancer and eight mesothelioma cell line RNAs detected ubiquitous expression of the beta -cat enin messages except NCI-H28, although Western blot analysis showed that re latively less amounts of protein products were expressed in some of lung ca ncer cell lines, Our findings suggest that the beta -catenin gene is infreq uently mutated in lung cancer and that the NCI-H28 homozygous deletion of t he beta -catenin gene might indicate the possibility of a new tumor suppres sor gene residing in this region at 3p21.3, where various types of human ca ncers show frequent allelic loss.