Expression ofp16INK4A and alterations of the 9p21-23 chromosome region in non-small-cell lung carcinomas: Relationship with tumor growth parameters and ploidy status

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Abstract
The 9p21‐23 chromosome region harbors a number of known and putative tumor‐suppressor genes (TSGs). The best characterized gene in this area is p16INK4A (CDKN2A). Alterations of its product have been observed in various malignancies, including non‐small‐cell lung carcinomas (NSCLCs). We earlier investigated the mechanisms underlying p16INK4A inactivation. In the present study, we examined, in a series of 87 NSCLCs, its relationship with the kinetic parameters [proliferation index (PI) and apoptotic index (Al)] and the ploidy status of the tumors. In addition, we extended our previous LOH analysis of the 9p21‐23 region by examining flanking areas of p16INK4A. Aberrant p16 expression was observed in 41.4% of the carcinomas. A significant association was found with increased PI (p = 0.037), but not with apoptosis. Aneuploid tumors were more frequently correlated with abnormal p16 staining (p = 0.05). A high frequency of allelic imbalance (Alm) was noticed at the D9S161 (51.3%) and D9S157 (64.5%) loci, which lie approximately 4cM centromeric and 7cM telomeric, respectively, to CDKN2A. Abnormal p16INK4A expression was strongly correlated with Alm at D9S161 (p = 0.004). Allelic losses at D9S157 occurred more frequently in early stages (p = 0.018) and were significantly associated with deletions at D9S161 (p = 0.035). We conclude that, in a sub‐set of NSCLCs, (i) abnormal p16 expression contributes to tumor growth mainly by increasing the proliferative activity in the initial stages of carcinogenesis; (ii) the association with aneuploidy merely reflects the impact of aberrant p16 on proliferative activity; and (iii) other putative TSGs possibly reside within the 9p21‐23 region that possibly co‐operate in certain cases with CDKN2A in the development of NSCLCs. Int. J. Cancer (Pred. Oncol.) 89:133–141, 2000.

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