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

G. A. Niehans, R. A. Kratzke, M. K. Froberg, D. M. Aeppli, P. L. Nguyen, J. Geradts

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Abstract

The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16(INK4a), are commonly altered in human malignancies, abrogating 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 well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16(INK4a), which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16(INK4a), or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16(INK4a) and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16(INK4a) and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16(INK4a) can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.

Original languageEnglish (US)
Pages (from-to)1175-1184
Number of pages10
JournalBritish Journal of Cancer
Volume80
Issue number8
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

Transitional Cell Carcinoma
Cyclin D1
Retinoblastoma
Urinary Bladder
Retinoblastoma Protein
Proteins
G1 Phase Cell Cycle Checkpoints
Carcinoma
Cell Cycle Checkpoints
Cell Cycle Proteins
Cystectomy
Survival Analysis
S Phase
Neoplasms
Cell Cycle
Multivariate Analysis
Immunohistochemistry
Staining and Labeling
Phenotype

Keywords

  • Bladder neoplasms
  • Cyclin D1
  • p16(1NK4)
  • p53
  • Retinoblastoma protein

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Niehans, G. A., Kratzke, R. A., Froberg, M. K., Aeppli, D. M., Nguyen, P. L., & Geradts, J. (1999). G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. British Journal of Cancer, 80(8), 1175-1184. https://doi.org/10.1038/sj.bjc.6990483

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. / Niehans, G. A.; Kratzke, R. A.; Froberg, M. K.; Aeppli, D. M.; Nguyen, P. L.; Geradts, J.

In: British Journal of Cancer, Vol. 80, No. 8, 1999, p. 1175-1184.

Research output: Contribution to journalArticle

Niehans, G. A. ; Kratzke, R. A. ; Froberg, M. K. ; Aeppli, D. M. ; Nguyen, P. L. ; Geradts, J. / G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder. In: British Journal of Cancer. 1999 ; Vol. 80, No. 8. pp. 1175-1184.
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abstract = "The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16(INK4a), are commonly altered in human malignancies, abrogating 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 well. Rb protein loss occurred in 23/79 cases (29{\%}); it was inversely correlated with loss of p16(INK4a), which occurred in 15/79 cases (19{\%}). One biphenotypic case, with Rb+p16- and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27{\%}), all of which retained Rb protein. Fifty of 79 tumours (63{\%}) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16(INK4a), or cyclin D1 status. Overall, 70{\%} of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16(INK4a) and cyclin D1). Only 15{\%} of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16(INK4a) and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16(INK4a) can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins.",
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