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(American Journal of Pathology. 2007;171:1650-1658.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070338

Genomic and Proteomic Profiles Reveal the Association of Gelsolin to TP53 Status and Bladder Cancer Progression

Marta Sanchez-Carbayo*{dagger}, Nicholas D. Socci{ddagger}, Lee Richstone{dagger}, Marta Corton*, Nille Behrendt{dagger}, Julia Wulkfuhle§, Bernard Bochner, Emmanuel Petricoin§ and Carlos Cordon-Cardo{dagger}

From the Tumor Markers Group,* Spanish National Cancer Center, the Division of Molecular Pathology,{dagger} the Computational Biology Center,{ddagger} and the Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York; and the Center for Applied Proteomics and Molecular Medicine,§ George Mason University, Manassas, Virginia

Bladder cancer transformation and immortalization require the inactivation of key regulatory genes, including TP53. Genotyping of a large cohort of bladder cancer patients (n = 256) using the TP53 GeneChip showed mutations in 103 cases (40.2%), the majority of them mapping to the DNA-binding core domain. TP53 mutation status was significantly associated with tumor stage (P = 0.0001) and overall survival for patients with advanced disease (P = 0.01). Transcript profiling using oligonucleotide arrays was performed on a subset of these cases (n = 46). Supervised analyses identified genes differentially expressed between invasive bladder tumors with wild-type (n = 24) and mutated TP53 (n = 22). Pathway analyses of top-ranked genes supported the central role of TP53 in the functional network of such gene patterns. A proteomic strategy using reverse phase arrays with protein extracts of bladder cancer cell lines validated the association of identified differentially expressed genes, such as gelsolin, to TP53 status. Immunohistochemistry on tissue microarrays (n = 294) revealed that gelsolin was associated with tumor stage and overall survival, correlating positively with TP53 status in a subset of these patients. This study further reveals that TP53 mutations are frequent events in bladder cancer progression and identified gelsolin related to TP53 status, tumor staging, and clinical outcome by independent high-throughput strategies.






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Copyright © 2007 by the American Society for Investigative Pathology.