THE GENETIC-BASIS OF HUMAN KERATINOCYTE IMMORTALIZATION IN SQUAMOUS-CELL CARCINOMA DEVELOPMENT - THE ROLE OF TELOMERASE REACTIVATION

Normal human keratinocytes have a finite replicative lifespan which cu lminates in senescence. Chromosomal telomere length may act as a media tor of replicative senescence, signalling cell cycle arrest in G1 when one or more telomeres become too short. Telomeric attrition in normal keratinocytes may be due to inadequate levels of telomerase activity and possibly also to oxidative damage. In advanced squamous cell carci noma replicative senescence breaks down to yield immortal variants, in which several dominantly acting genes are functionally compromised, i ncluding p53 and the cyclin D-Cdk4/6 inhibitor CDKN2A/p16. The increas ed activity of both of these proteins would be expected to contribute to the G1 arrest in senescence and we have shown that levels of p16 ar e dramatically increased in senescent keratinocytes. In addition, two other genes which control a cell cycle G1 checkpoint independently of p53 and pRb appear dysfunctional. These genes are uncloned but map to chromosome 4q and 7q31.1 and appear to represent senescence complement ation groups B and D, respectively. In immortal neoplastic keratinocyt es, telomerase is strongly upregulated and there is evidence for a sup pressor of the enzyme on the short arm of chromosome 3 mapping to 3p21 .2-p21.3. We have also mapped the human telomerase RNA gene to 3q26.3 and found it to be overrepresented or amplified in a proportion of squ amous cell tumours and cell lines. These observations may explain why isochromosome 3q is so common in human squamous carcinoma. None of the se genetic alterations are seen in carcinomas which senesce and sugges t that multiple genetic alterations are required for keratinocyte immo rtality. (C) 1997 Elsevier Science Ltd.