MUTATIONS IN THE P16(INK4) MTS1/CDKN2, P15(INK4B)/MTS2, AND P18 GENESIN PRIMARY AND METASTATIC LUNG-CANCER/

We examined the genomic status of cyclin-dependent kinase- 4 and -6 in hibitors, p16(INK4), p15(INK4B), and p18, in 40 primary lung cancers a nd 31 metastatic lung cancers. Alterations of the p16(INK4) gene were detected in 6 (2 insertions and 4 homozygous deletions) of 22 metastat ic non-small cell lung cancers (NSCLCs; 27%), but none were detected i n 25 primary NSCLCs, 15 primary small cell lung cancers (SCLCs), or 9 metastatic SCLCs, indicating that mutation in the p16(INK4) gene is a late event in NSCLC carcinogenesis. Although three intragenic mutation s of the p15(INK4B) gene were detected in 25 primary NSCLCs (12%) and five homozygous deletions of the p15(INK4B) gene were detected in 22 N SCLCs (23%), no genetic alterations of the p15(INK4B) gene were found in primary and metastatic SCLCs. The p18 gene was wild type in these 7 1 lung cancers, except 1 metastatic NSCLC which showed loss of heteroz ygosity. We also examined alterations of these three genes and express ion of p16(INK4) in 21 human lung cancer cell lines. Alterations of th e p16(INK4) and p15(INK4B) genes were detected in 71% of the NSCLC tel l lines (n = 14) and 50% of the NSCLC cell lines (n = 14), respectivel y, but there were none In the 7 SCLC cell lines studied. No p18 mutati ons were detected in these 21 cell lines. These results indicate that both p16(INK4) and P14(INK4B) gene mutations are associated with tumor progression of a subset of NSCLC, but not of SCLC, and that p15(INK4B ) mutations might also be an early event in the molecular pathogenesis of a subset of NSCLC.