Combined proteome and transcriptome analyses for the discovery of urinary biomarkers for urothelial carcinoma

• Published in: British journal of cancer Vol. 108; no. 9; pp. 1854 - 1861
• Main Authors: Shimwell, N J, Bryan, R T, Wei, W, James, N D, Cheng, K K, Zeegers, M P, Johnson, P J, Martin, A, Ward, D G
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-05-2013; Nature Publishing Group
• Subjects: 631/45/475; 692/699/67/1857; 692/699/67/589/1336; Biological and medical sciences; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - urine; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Body fluids; Cancer Research; Carcinoma, Transitional Cell - pathology; Carcinoma, Transitional Cell - urine; Cell Line, Tumor; Cellular biology; Cytokines - urine; Drug Resistance; Epidemiology; Gene expression; Gene Expression Profiling; Hematuria; Humans; Medical sciences; Molecular Diagnostics; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nephrology. Urinary tract diseases; Oncology; Protein Array Analysis; Proteinase Inhibitory Proteins, Secretory - urine; Proteins; Proteinuria; Proteome - analysis; RNA, Messenger - analysis; Surveillance; Transcriptome; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - urine; Urinary tract. Prostate gland; Urine; Urologic Neoplasms - pathology; Urologic Neoplasms - urine; Urothelium - pathology; United Kingdom > UK; midkine; biomarker; secretome; urine; bladder cancer; Urine; Urinary system disease; Transcriptome; Biological marker; Proteome; Secretome; Urinary tract disease; Malignant tumor; Transitional cell carcinoma; Discoveries; Bladder cancer; Cancerology; Bladder disease; Midkine; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.157

Background:
Proteomic discovery of cancer biomarkers in body fluids is challenging because of their low abundance in a complex background. Altered gene expression in tumours may not reflect protein levels in body fluids. We have tested combining gene expression profiling of tumours with proteomic analysis of cancer cell line secretomes as a strategy to discover urinary biomarkers for bladder cancer.
Methods:
We used shotgun proteomics to identify proteins secreted by three bladder cancer cell lines. Secreted proteins with high mRNA levels in bladder tumours relative to normal urothelium were assayed by ELISA in urine samples from 642 patients.
Results:
Midkine and HAI-1 were significantly increased in bladder cancer patients, with the highest levels in invasive disease (area under the receiver operating characteristic curve 0.89
vs
non-cancer). The urinary concentration of both proteins was too high to be explained by bladder cancer associated haematuria and most likely arises by direct tumour secretion.
Conclusions:
This ‘dual-omic’ strategy identified tumour secreted proteins whose urine concentrations are increased significantly by bladder cancer. Combined secretome-transcriptome analysis may be more useful than direct proteomic analysis of body fluids for biomarker discovery in both bladder cancer and other tumour types.