Evidence for a putative senescence gene locus within the chromosomal region 10p14-p15

High-risk human papillomavirus (HPV.) types 16 and 18 are involved in the m ultistep process of cervical cancer. Transfection of normal keratinocytes w ith high-risk HPV-DNA generally gives rise to immortal cultures. This may b e explained by the loss of senescence genes as a consequence of HPV-induced genetic instability. On the basis of the dominance of cellular senescence over immortality, fusion of normal keratinocytes with HPV-immortalized cell s results in complementation of these putative gene defects. In a previous study, we showed that underrepresentation of chromosome 10 is a characteris tic phenomenon during the early phase of immortalization. Here we show that introduction of a normal copy of chromosome 10 into HPV16-immortalized cel ls (HPKII) by Microcell-mediated chromosome transfer resulted in senescence of a significant number of hybrids. By using several derivatives of chromo some 10 for further fusion experiments, the chromosomal region responsible for senescence could be assigned to 10p14-p15. The potential significance o f loss of gene function in this region is underlined by the high frequency (38.7%) of loss of heterozygosity in cervical cancers including early stage tumors.