title: Multicenter validation of cyclin D1, MCM7, TRIM29, and UBE2C as prognostic protein markers in non-muscle-invasive bladder cancer.
abstract: Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have previously been included in gene expression signatures for outcome prediction in stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle-invasive bladder cancer (log-rank test; P < 0.001) in the Danish training cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P = 0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, Spain, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation of their clinical relevance.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, DK-8200 Aarhus, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Fristrup
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtröder
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinert
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Carbayo
authors.forename: Ulrika
authors.initials: U
authors.lastname: Segersten
authors.forename: Per-Uno
authors.initials: PU
authors.lastname: Malmström
authors.forename: Joan
authors.initials: J
authors.lastname: Palou
authors.forename: Miguel
authors.initials: M
authors.lastname: Alvarez-Múgica
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Pan
authors.forename: Benedicte P
authors.initials: BP
authors.lastname: Ulhøi
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015331:Cohort Studies; D019938:Cyclin D1 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003718:Denmark; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D064168:Minichromosome Maintenance Complex Component 7; D015999:Multivariate Analysis; D009132:Muscles / Q000473:pathology; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism*; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012307:Risk Factors; D013030:Spain; D013548:Sweden; D013624:Taiwan; D014157:Transcription Factors / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C087296:TRIM29 protein, human; D014157:Transcription Factors; D019938:Cyclin D1; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7