| Abstract: |
To identify gene expression changes along progression of bladder cancer, we compared the expression profiles of early-stage and advanced bladder tumors using cDNA microarrays containing 17,842 known genes and expressed sequence tags. The application of bootstrapping techniques to hierarchical clustering segregated early-stage and invasive transitional carcinomas into two main clusters. Multidimensional analysis confirmed these clusters and more importantly, it separated carcinoma in situ from papillary superficial lesions and subgroups within early-stage and invasive tumors displaying different overall survival. Additionally, it recognized early-stage tumors showing gene profiles similar to invasive disease. Different techniques including standard t-test, single-gene logistic regression, and support vector machine algorithms were applied to identify relevant genes involved in bladder cancer progression. Cytokeratin 20, neuropilin-2, p21, and p33ING1 were selected among the top ranked molecular targets differentially expressed and validated by immunohistochemistry using tissue microarrays (n = 173). Their expression patterns were significantly associated with pathological stage, tumor grade, and altered retinoblastoma (RB) expression. Moreover, p33ING1 expression levels were significantly associated with overall survival. Analysis of the annotation of the most significant genes revealed the relevance of critical genes and pathways during bladder cancer progression, including the overexpression of oncogenic genes such as DEK in superficial tumors or immune response genes such as Cd86 antigen in invasive disease. Gene profiling successfully classified bladder tumors based on their progression and clinical outcome. The present study has identified molecular biomarkers of potential clinical significance and critical molecular targets associated with bladder cancer progression. |
| Keywords: |
immunohistochemistry; cancer survival; aged; aged, 80 and over; middle aged; survival rate; unclassified drug; human cell; dna-binding proteins; advanced cancer; cancer growth; proteins; cell cycle proteins; gene overexpression; gene expression; gene expression profiling; tumor markers, biological; tumor cells, cultured; bladder cancer; tumor marker; urinary bladder neoplasms; nuclear proteins; cancer invasion; gene expression regulation, neoplastic; immune response; oligonucleotide array sequence analysis; disease progression; intracellular signaling peptides and proteins; expressed sequence tag; gene identification; nucleotide sequence; carcinoma in situ; tumor suppressor proteins; cytokeratin 20; dna microarray; carcinoma, transitional cell; retinoblastoma protein; protein p21; unindexed sequence; transitional cell carcinoma; genes, tumor suppressor; cd86 antigen; growth inhibitors; neuropilin 2; humans; human; male; female; priority journal; article; protein p33
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