Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle-Invasive Bladder Cancer
Por:
Fristrup, N, Birkenkamp-Demtroder, K, Reinert, T, Sanchez-Carbayo, M, Segersten, U, Malmstrom, PU, Palou, J, Alvarez-Mugica, M, Pan, CC, Ulhoi, BP, Borre, M, Orntoft, TF, Dyrskjot, L
Publicada:
1 feb 2013
Resumen:
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. (Am J Pathol 2013, 182: 339-349; http://dx.doi.org/10.1016/j.ajpath.2012.10.017)
Filiaciones:
Fristrup, N:
Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark
Birkenkamp-Demtroder, K:
Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark
Reinert, T:
Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark
Sanchez-Carbayo, M:
Spanish Natl Canc Res Ctr, Tumor Markers Grp, Madrid, Spain
Segersten, U:
Uppsala Univ, Dept Surg Sci, Uppsala, Sweden
Malmstrom, PU:
Uppsala Univ, Dept Surg Sci, Uppsala, Sweden
Palou, J:
Fundacio Puigvert, Dept Urol, Barcelona, Spain
Alvarez-Mugica, M:
Univ Oviedo, Hosp Cent Asturias, Dept Urol, E-33080 Oviedo, Spain
Pan, CC:
Taipei Vet Gen Hosp, Dept Pathol, Taipei, Taiwan
Ulhoi, BP:
Aarhus Univ Hosp, Inst Pathol, DK-8200 Aarhus, Denmark
Borre, M:
Aarhus Univ Hosp, Dept Urol, DK-8200 Aarhus, Denmark
Orntoft, TF:
Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark
Dyrskjot, L:
Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark
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