Molecular and immunohistochemical analysis of the prognostic value of cell-cycle regulators in urothelial neoplasms of the bladder.
OBJECTIVE
To evaluate the prognostic and predictive value of molecular and immunohistochemical markers related to cell-cycle control in terms of recurrence, progression, and survival in urothelial neoplasms of the bladder (UNB).


METHODS
Clinical and pathological findings of 84 patients with UNB were assessed. Homozygous deletion (HD) and promoter methylation of p14ARF, p15INK4B, p16INK4A, loss of heterozygosity of the locus 9p21, p53 mutations, and immunohistochemical expression of p53, p16, p14, p21, p27, pRb, Ki67, MDM2, and cyclin D1 proteins were evaluated in relation to overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS).


RESULTS
In the univariate analysis, RFS was shorter in cases with p14ARF (p=0.006), p15INK4B (p=0.003), p16INK4A (p=0.03) HD, low p14 immunoreactivity index (IRI) (p=0.01) and high Ki67 IRI (p=0.04); HD of the 9p21 locus genes and p14 IRI remained as independent prognostic factors for early UNB recurrence (p=0.006) whereas tumour stage (p=0.00001) and cyclin D1 IRI (p=0.049) were related to worse PFS in the multivariate analysis. In the univariate analysis, IRI for Ki67 (p=0.002), cyclin D1 (p=0.06), p53 (p=0.00008), p16 (p=0.02), p27 (p=0.0005) MDM2 (p=0.01) and p53 mutations (p=0.03) were related to poor OS, and only the Ki67 IRI retained their independent value in the multivariate analysis.


CONCLUSIONS
9p21 HD and p14 IRI constitute independent predictive factors for UNB recurrence and cyclin D1 IRI and tumour stage for progression. In addition, Ki67 IRI and tumour stage are independent prognostic factors for overall survival in UNB.
Yurakh
Andriy O
AO
Institute of Urology, Academy of Medical Science of Ukraine, Kyiv, Ukraine. yurakh@list.ru
Ramos
David
D
Calabuig-Fariñas
Silvia
S
López-Guerrero
José Antonio
JA
Rubio
José
J
Solsona
Eduardo
E
Romanenko
Alina M
AM
Vozianov
Alexander F
AF
Pellin
Antonio
A
Llombart-Bosch
Antonio
A
D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D018797:Cell Cycle Proteins / Q000378:metabolism*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D025202:Molecular Diagnostic Techniques / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000378:metabolism / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012175:Retinoblastoma / Q000378:metabolism; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D019459:Urothelium / Q000473:pathology
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2