Molecular Alterations In Papillary Bladder Cancers

In contrast to invasive bladder cancers, papillary transitional cell carcinomas contain a limited number of chromosomal aberrations. This is particularly true for well-differentiated tumors which are usually not invasive, although clearly hyperplastic and with diminished terminal differentiaton. On average, the number of genetic changes in this tumor type increases with tumor grade (^1.4).

Independent of tumor grade, however, loss of chromosome 9 is very frequent. As a result, p16INK4A and p14ARF may not be functional, and the enigmatic tumor suppressor gene at 9q (^14.2) could be affected. Expression of Cyclin D1 as well as MYC is usually increased. These are more likely indicators of increased cell cycle activity than its cause. In a small percentage of cases, mutations activating HRAS are detected, which could be responsible for the evident hyperproliferation. TP53 mutations are much rarer than in invasive bladder cancers and are found predominantly in high-grade tumors on the brink of becoming invasive.

Normally, urothelium is a quiescent tissue with a very low turnover. Following tissue damage, regeneration is stimulated by growth factors produced by the underlying mesenchyme, e.g. FGFs. Urothelial cells also produce autocrine factors, predominantly heparin-binding epidermal growth factor and related peptides of the EGF family (^-18.4). These act in normal urothelium through the EGFR which is mainly expressed in basal cells. Members of the FGF family may also regulate the thickness of the epithelial layer during development of the tissue.

Many urothelial cancers overexpress the EGFR, e.g. as a consequence of chromosome 7p gain. The strength of EGFR overexpression rather closely parallels the rate of proliferation detected by immunohistochemical markers such as the DNA replisome subunit PCNA or the protein Ki67, which is thought to be needed for increased nucleolar activity in proliferating cells. In bladder cancers, the EGFR is rarely activated by mutation.

In contrast, «60% of papillary urothelial cancers contain missense mutations in the FGFR3 receptor leading to its constitutive activity. The mutations in FGFR3 occur at very specific sites (Figure 14.9) and appear to prolong the half-life of the receptor and of its activated state. The mutations in the FGFR3 extracellular ligand-

Figure 14.9 Mutations of FGFR3 frequent in papillary bladder cancers

binding domain may also alter its specificity for the >20 members of the FGF family. Mutations in FGFR3 are otherwise only found in cervical cancers. However, these and further mutations have also been encountered in hereditary achondroplasia. In this syndrome, specific point mutations in the receptor lead to shortened bones, particularly in the thighs and upper arms, because over-activity of FGFR3 causes premature differentiation of cartilage tissue in the growth zones. The same mutations in bladder cancers increase proliferation rather than differentiation of urothelial cells.

Surprisingly, bladder cancers with FGFR3 mutations have a distinctly lower risk of progression than those without. Thus, these mutations can serve as molecular markers for cancers that can be treated conservatively, i.e. solely by resection and by monitoring (cf. Figure 14.5). In fact, the discrimination can be improved by using molecular markers associated with the opposite behavior. Mutations of TP53, which in bladder cancer can relatively reliably be detected by accumulation of mutant protein, or the proliferation index as determined by PCNA staining have been proposed.

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