title: 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.
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 p16(INK4A) (CDKN2A). Alterations of its product have been observed in various malignancies, including non-small-cell lung carcinomas (NSCLCs). We earlier investigated the mechanisms underlying p16(INK4A) 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 p16(INK4A). 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 p16(INK4A) 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.
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Mariatos
authors.forename: V G
authors.initials: VG
authors.lastname: Gorgoulis
authors.forename: P
authors.initials: P
authors.lastname: Zacharatos
authors.forename: A
authors.initials: A
authors.lastname: Kotsinas
authors.forename: T
authors.initials: T
authors.lastname: Vogiatzi
authors.forename: G
authors.initials: G
authors.lastname: Rassidakis
authors.forename: P
authors.initials: P
authors.lastname: Foukas
authors.forename: T
authors.initials: T
authors.lastname: Liloglou
authors.forename: D
authors.initials: D
authors.lastname: Tiniakos
authors.forename: N
authors.initials: N
authors.lastname: Angelou
authors.forename: E N
authors.initials: EN
authors.lastname: Manolis
authors.forename: M
authors.initials: M
authors.lastname: Veslemes
authors.forename: J K
authors.initials: JK
authors.lastname: Field
authors.forename: C
authors.initials: C
authors.lastname: Kittas
mesh_terms: D000368:Aged; D000483:Alleles; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002455:Cell Division; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16 / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011003:Ploidies; D016019:Survival Analysis
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16