Figure 16
Inactivation of FR and RB1 genes in the development of bladder cancer. (a) The analysis of LOP and inactivation of FR and RB1 genes documented by DNA sequencing, methylation, and immunohistochemical analyses based on data shown in Figure 12. LGPTCC, low-grade (grades 1 and 2) superficial (Ta–T1a) papillary TCC; HGNPTCC, high-grade (grade 3) non-papillary invasive (T1b and higher). (b) Sequential inactivation of P2RY5 and RB1 in the development of bladder cancer from in situ neoplasia. The loss of wild-type P2RY5 copy and the retention of the 1722T variant allele inactivate the P2RY5 gene. Low-power view of invasive bladder cancer and adjacent LGIN and HGIN (upper panel). Microdissected DNA corresponding to LGIN shows loss of wild-type P2RY5 allele and retention of normal RB expression pattern (lower panel, left). Microdissected DNA corresponding to HGIN shows similar loss of wild-type P2RY5 allele and additional loss of RB protein expression (lower panel, center). Similar loss of wild-type P2RY5 allele and RB protein expression is seen in invasive TCC (lower panel, right). Arrows indicate retention of normal RB protein expression in endothelial cells adjacent to tumor. (Reprinted with permission from Lee S, Jeong J, Majewski T, et al. Proc Natl Acad Sci USA 2007;104:13732–13737.) (c) The FR gene hypothesis postulates that their inactivation by allelic loss, methylation, and less frequently by mutations or polymorphism contributes to the initial clonal expansion of in situ neoplasia microscopically consistent with LGIN common to both papillary and non-papillary pathways. The loss of tumor suppressor genes, such as RB1, is secondary and associated with the development of a successor clone showing features of severe dysplasia/carcinoma in situ (HGIN) progressing to invasive TCC.
