Expression of p16(INK4A) and alterations of the 9p21-23 chromosome region in non-small-cell lung carcinomas: Relationship with tumor growth parameters and ploidy status

The 9p21-23 chromosome region harbors a number of known and putative tumor- suppressor genes (TSGs). The best characterized gene in this area is p16(IN K4A) (CDKN2A). Alterations of its product have been observed in various mal ignancies, including non-small-cell lung carcinomas (NSCLCs). We earlier in vestigated the mechanisms underlying p16(INK4A) inactivation. In the presen t study, we examined, in a series of 87 NSCLCs, its relationship with the k inetic parameters [proliferation index (PI) and apoptotic index (AI)] and t he ploidy status of the tumors. In addition, we extended our previous LOH a nalysis of the 9p21-23 region by examining flanking areas of p16(INK4A). Ab errant p16 expression was observed in 41.4% of the carcinomas. A significan t association was found with increased PI (p = 0.037), but not with apoptos is. Aneuploid tumors were more frequently correlated with abnormal p16 stai ning (p = 0.05), A high frequency of allelic imbalance (AIm) was noticed at : the D9S161 (51.3%) and D9S157 (64.5%) loci, which lie approximately 4cM c entromeric and 7cM telomeric, respectively, to CDKN2A, Abnormal p16(INK4A) expression was strongly correlated with Aim at D9S161 (p = 0.004). Allelic losses at D9S157 occurred more frequently in early stages (p = 0.018) and w ere significantly associated with deletions at D9S161 (p = 0.035). We concl ude that, in a sub-set of NSCLCs, (i) abnormal p16 expression contributes t o tumor growth mainly by increasing the proliferative activity in the initi al stages of carcinogenesis; (ii) the association with aneuploidy merely re flects the impact of aberrant p16 on proliferative activity; and (iii) othe r putative TSGs possibly reside within the 9p21-23 region that possibly co- operate in certain cases with CDKN2A in the development of NSCLCs. (C) 2000 Wiley-Liss, Inc.