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
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.