D-type cyclins in superficial and muscle-invasive bladder urothelial carcinoma: correlation with clinicopathological data and prognostic significance

Levidou, Georgia; Saetta, Angelica A.; Κάρλου, Μαρία; Thymara, Irene; Pratsinis, Harris; Pavlopoulos, Petros M.; Isaiadis, Dimitrios; Diamantopoulou, Kalliopi; Patsouris, Efstratios; Korkolopoulou, Penelope

doi:10.1007/s00432-010-0814-y

Cited by 20 publications

(14 citation statements)

References 23 publications

(28 reference statements)

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“…As shown in our previous study [19], cyclin D1 expression decreased with increasing histological grade (Kruskal–Wallis, anova P < 0.001) and advancing T‐category in the entire cohort (Kruskal–Wallis, anova , P < 0.001). Both RPA1 and RPA2 expressions were positively correlated with cyclin D1 expression (ρ= 0.3535, P < 0.001 and ρ= 0.9340, P < 0.001).…”

Section: Resultssupporting

confidence: 79%

“…The significant associations observed between these molecules possibly reflect their similar kinetics. As we have previously reported, cyclin D1 seems to play an important role in bladder carcinoma tumorigenesis [19]. It could be hypothesized that RPA proteins may play a synergistic role in this field, being concomittantly up‐regulated to accomplish their potential proliferative task.…”

Section: Discussionmentioning

confidence: 71%

“…Immunohistochemical detection of RPA1 and RPA2 proteins was performed by standard streptavidin‐peroxidase method, using the monoclonal antibodies anti‐RPA1 (P70 subunit, NA13, Oncogene) and anti‐RPA2 (P32 subunit, NA18, Oncogene) in a dilution of 1:50 for each antibody. The same cases have been stained for cyclin D1 for our previous investigation [19]. To enhance antigen retrieval sections underwent microwave treatment (using 1 m m EDTA, pH 8.0).…”

Section: Methodsmentioning

confidence: 99%

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Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma

et al. 2010

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( ρ = 0.354, P < 0.001 and ρ = 0.934, P < 0.001).• In survival analysis of the entire cohort decreased RPA2 and RPA1 correlated with a lesser probability of survival ( P < 0.001 and P = 0.018). In non-muscle-invasive tumours (Ta-T1) only lower RPA2 ( P < 0.001) was correlated with shortened survival, whereas in muscle-invasive tumours (T2-T4) decreased RPA2 and RPA1 expression levels were associated with adverse prognosis ( P = 0.035 and P = 0.042, respectively).• In multivariate survival analysis of the entire cohort and in non-muscle-invasive cases RPA2 expression remained significant, even when adjustment for cyclin D1 expression was applied. CONCLUSIONS• RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis. Showing similar kinetics with cyclin D1.• RPA2 expression emerges as a valuable marker of favourable prognosis in the entire cohort and in non-muscle-invasive tumours, supplementing the information obtained by standard clinicopathological prognosticators. KEYWORDS RPA, immunoexpression, bladder urothelial carcinomaWhat's known on the subject? and What does the study add? The prognostic utility of cyclin D1 in non-muscle and muscle-invasive urothelial bladder carcinomas has already been examined by our group and our investigators previously. Moreover, recent investigations have shown that RPA protein expression may be implicated in the pathogenesis of various malignant tumours. In this study, RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis, showing similar kinetics with cyclin D1, whereas RPA2 expression emerges as a valuable marker of favourable prognosis in the entire cohort and in non-muscle-invasive tumours, supplementing the information obtained by standard clinicopathological prognosticators. OBJECTIVE• To elucidate the role of replication protein A (RPA) in both superficial (Ta-T1) and muscle-invasive (T2-T4) urothelial carcinomas (UCs), investigating its potential prognostic usefulness. PATIENTS AND METHODS• Paraffin-embedded tissue from 156 patients with bladder UC was immunostained for RPA1 and RPA2. RESULTS• RPA1 and RPA2 labelling indexes (LIs) decreased with increasing histological grade (both P < 0.001) and T-category in the entire cohort ( P = 0.008 and P < 0.001, respectively) and in muscle-invasive carcinomas ( P = 0.014 and P = 0.012, respectively).• RPA1 expression was positively correlated with RPA2 (Spearman's correlation coefficient ρ = 0.309, P < 0.001). Both RPA1 and RPA2 LIs were positively correlated with cyclin D1 expression

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

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Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma

et al. 2010

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“…The prognostic impact has primarily been evaluated in non-muscle invasive bladder cancer for CyclinD1 and with regard to recurrence-and progression-free survival. However, data were inconsistent showing CyclinD1 expression as a marker of adverse [20][21][22] or favorable [23][24][25][26][27] prognosis or without prognostic impact. 28 Only two studies investigated the prognostic relevance of CCND1 amplification in bladder cancer: while CCND1 amplification was an adverse risk factor in non-muscle invasive bladder cancers, 29 it failed to predict survival in muscle invasive tumors.…”

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confidence: 99%

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

et al. 2014

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The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60-70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5-20% immunostained tumor nuclei; Po0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P ¼ 0.001) and metastases (P ¼ 0.02) and high nuclear CyclinD1 in metastases (P ¼ 0.01) predicted early cancerrelated death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.

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“…D-type cyclins are also prognostic markers in advanced bladder cancer. Higher protein expression of cyclin D1 ( p = 0.023) and D2 ( p = 0.042) and lower levels of D3 ( p = 0.032) correlate with better DSS rates in a population of 57 MIBC patients [20]. …”

Section: Prognostic Biomarkers That Identify High-risk Patientsmentioning

confidence: 99%

Biomarkers for prognosis and treatment selection in advanced bladder cancer patients

Ru¹,

Dancik²,

Theodorescu

2011

Current Opinion in Urology

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Purpose of review Patients with locally “advanced” or muscle invasive bladder cancer have higher mortality rates than patients with non-muscle invasive (“superficial”) bladder cancer. Biomarkers can stratify clinical outcomes and thus promise to more accurately prognosticate and thus help assign patients to the appropriate treatments. The aim of this review is to summarize biomarker developments in the past year and to discuss their implications in prognosis and treatment selection in locally advanced bladder cancer. Recent findings Prognostic biomarkers for bladder cancer are identified at the DNA, RNA and/or protein levels. Some are new markers; others are established markers with new roles in bladder cancer. Markers can report on the risk of disease recurrence or metastasis, or treatment responsiveness and thus are useful in determining “who to treat” and “what to treat with”. Summary The list of biomarkers for prognosis and treatment selection for advanced bladder cancer is growing. For most, their clinical relevance is unclear due to their lack of validation in external datasets. MicroRNAs and new techniques including next-generation sequencing offer additional opportunities for biomarker discovery, validation, and clinical applications.

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D-type cyclins in superficial and muscle-invasive bladder urothelial carcinoma: correlation with clinicopathological data and prognostic significance

Cited by 20 publications

References 23 publications

Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma

Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response

Biomarkers for prognosis and treatment selection in advanced bladder cancer patients

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