As yet, no irreversible abnormalities in the cell cycle have been demonstrated during the stage of promotion; however, the promoting agent phenobarbital does appear to affect one of the check- points in the cell cycle (Goldsworthy et al., 1999). During the stage of progression, both muta- tions in and altered regulation of cell cycle components have been described. A listing of genes, together with their abnormalities and the neoplasms in which such abnormalities are noted, is given in Table 9.6. Several of these genes, such as the retinoblastoma and p53 genes, have been discussed previously in relation to the genetic changes occurring in neoplasia (Chapters 5 and 6). From the table it can be noted, however, that several of the cyclins, most notably cyclin D1, exhibit increased expression largely through the mechanism of amplification and translocation.
As noted from our previous discussion (Figure 9.5), one may readily understand that increased levels of these cyclins, especially when other factors regulating the cell cycle show abnormali- ties—e.g., p16, p53, and p21—can drive the enhanced replicative activity of neoplasms in the stage of progression. Most studies of p21 in human neoplasms have found few if any somatic mutations in this gene, although some polymorphisms in the gene have been described (cf. Gar- tel et al., 1996). The report by Jung et al. (1995) of an increased expression of p21 in a variety of cell lines from human gliomas suggests, just as with the increased transcription of cyclin A in leukemias (Paterlini et al., 1995), that amplification of the gene does occur in these neoplastic cells. The amplification of CDK4 noted in the number of gliomas and sarcomas (cf. Hall and Peters, 1996) would be expected to further the enhanced activity of the cycle by its association with cyclin D1. The hBUB1 gene controls mitotic delay in response to spindle alterations. The protein product exhibits kinase activity and was found to be mutated in several colorectal cancer cell lines and associated with karyotypic instability (Cahill et al., 1998). Many of the alterations noted in the table are the result of processes probably occurring during the stage of progression concomitant with increased karyotypic instability. These include translocations, amplification, and deletions. Thus, a direct causative relation between the critical feature of the stage of pro- gression, karyotypic instability, and deregulation of the cell cycle is readily understood from data such as those presented in Table 9.6.