CYCLIN D1 AND RETINOBLASTOMA SUSCEPTIBILITY GENE ALTERATIONS IN NONSMALL CELL LUNG-CANCER

Among the major regulators of the G(1) restriction point are cyclin D1 and the retinoblastoma gene product (RB). In non-small cell lung canc er (NSCLC), the cyclin D1 gene is amplified/over-expressed in almost 5 0% of cases, and RB is inactivated in 6-32% of cases, It is of interes t to evaluate concurrently the alterations of both genes on the same s eries of NSCLCs, to investigate whether cyclin D1 and RB alterations a re alternative pathways leading to inactivation of the G(1) restrictio n point or if they can occur in the same tumor, possibly exerting an a dditive effect on cancer progression, We investigated a series of 57 N SCLCs, analyzing cyclin D1 and RB at the gene and protein levels by So uthern blot, Northern blot and immunohistochemistry. The cyclin D1 gen e was amplified in 18 cases. cyclin D1 immunoreactivity was seen in 25 tumors, Amplification and expression were significantly associated. R B immunohistochemical expression was absent in 9 of 42 informative cas es. RB mRNA expression was low to absent in 9 of 45 informative cases. cyclin D1 amplification was associated with normal RB mRNA, and cycli n D1 over-expression was associated with normal RB immunoreactivity, s upporting the hypothesis that alterations of cyclin D1 and RB are alte rnative mechanisms by which tumor cells may escape the G(1) restrictio n point. A concurrent alteration of RB and cyclin D1 was seen in a sma ll subset of NSCLCs. Abnormalities of cyclin D1 and/or RB at the gene and/or expression level were present in more than 90% of cases, stress ing that cyclin D1 and/or RB alterations represent an important step i n lung tumorigenesis. (C) 1998 Wiley-Liss, Inc.