G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

Citation
Ga. Niehans et al., G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder, BR J CANC, 80(8), 1999, pp. 1175-1184
Citations number
54
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
BRITISH JOURNAL OF CANCER
ISSN journal
00070920 → ACNP
Volume
80
Issue
8
Year of publication
1999
Pages
1175 - 1184
Database
ISI
SICI code
0007-0920(199906)80:8<1175:GCPAPA>2.0.ZU;2-8
Abstract
The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cy clin D1 and p16(INK4a), are commonly altered in human malignancies, abrogat ing cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16(INK4a) protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as w ell. Rb protein loss occurred in 23/79 cases (29%); it was inversely correl ated with loss of p16(INK4a), which occurred in 15/79 cases (19%). One biph enotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cycl in D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 pro tein; p53 staining did not correlate with Rb, p16(INK4a), or cyclin D1 stat us. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16(INK4a) and cyclin D 1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype fo r all four proteins. In a multivariate survival analysis, cyclin D1 overexp ression was linked to less aggressive disease and relatively favourable out come. In our series, Rb, p16(INK4a) and p53 status did not reach statistica l significance as prognostic factors. In conclusion, G1 restriction point d efects can be identified in the majority of bladder carcinomas. Our finding s support the hypothesis that cyclin D1 and p16(INK4a) can cooperate to dys regulate the cell cycle, but that loss of Rb protein abolishes the G1 check point completely, removing any selective advantage for cells that alter add itional cell cycle proteins.