Abstract
We used protein expression profiles to develop a classification rule for the detection and prognostic assessment of bladder cancer in voided urine samples. Using the Ciphergen PBS II ProteinChip Reader, we analyzed the protein profiles of 18 pairs of samples of bladder tumor and adjacent urothelium tissue, a training set of 85 voided urine samples (32 controls and 53 bladder cancer), and a blinded testing set of 68 voided urine samples (33 controls and 35 bladder cancer). Using t-tests, we identified 473 peaks showing significant differential expression across different categories of paired bladder tumor and adjacent urothelial samples compared to normal urothelium. Then the intensities of those 473 peaks were examined in a training set of voided urine samples. Using this approach, we identified 41 protein peaks that were differentially expressed in both sets of samples. The expression pattern of the 41 protein peaks was used to classify the voided urine samples as malignant or benign. This approach yielded a sensitivity and specificity of 59% and 90%, respectively, on the training set and 80% and 100%, respectively, on the testing set. The proteomic classification rule performed with similar accuracy in low- and high-grade bladder carcinomas. In addition, we used hierarchical clustering with all 473 protein peaks on 65 benign voided urine samples, 88 samples from patients with clinically evident bladder cancer, and 127 samples from patients with a history of bladder cancer to classify the samples into Cluster A or B. The tumors in Cluster B were characterized by clinically aggressive behavior with significantly shorter metastasis-free and disease-specific survival.
Highlights
Current pathogenetic concepts postulate that common neoplasms of the bladder arise in its epithelial lining via two distinct but somewhat overlapping pathways: the papillary and nonpapillary pathways. [1] Approximately 80% of the tumors that arise in the bladder are exophytic papillary lesions that originate from hyperplastic urothelial changes
To identify the proteins that were abnormally expressed during early bladder cancer development, we analyzed the patterns of their expression in 18 paired samples of bladder tumor and adjacent urothelium tissue and compared them to their expression pattern in 13 samples of normal urothelium
Since voided urine sediments may contain a mixture of tumor and nontumor cells, including inflammatory, stromal, and peripheral blood cells as well as necrotic cells with degenerated proteins, we focused on the same 473 peaks identified in the tissue samples and examined their intensities in a training set of voided urine samples from 53 patients with clinically evident bladder cancer and 32 healthy individuals
Summary
Current pathogenetic concepts postulate that common neoplasms of the bladder arise in its epithelial lining (urothelium) via two distinct but somewhat overlapping pathways: the papillary and nonpapillary pathways. [1] Approximately 80% of the tumors that arise in the bladder are exophytic papillary lesions that originate from hyperplastic urothelial changes. [1] Approximately 80% of the tumors that arise in the bladder are exophytic papillary lesions that originate from hyperplastic urothelial changes. They typically recur but usually do not invade the bladder wall or metastasize. The remaining 20% of bladder tumors are aggressive, nonpapillary carcinomas with a propensity for invading and metastasizing. Invasive bladder cancers typically occur in patients without a history of papillary tumors and originate from in situ preneoplastic lesions ranging from mild to moderate dysplasia (low-grade intraurothelial neoplasia, LGIN) to severe dysplasia and carcinoma in situ (high-grade intraurothelial neoplasia, HGIN). [2] The majority of aggressive high-grade non-papillary bladder carcinomas present at an advanced stage and necessitate chemotherapy and/or radical cystectomy to improve survival. The morphology of exfoliated urothelial cells and their constituents as well as secreted products can be scrutinized in urine at no risk to the patient
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