Development and Validation of Urine-based Peptide Biomarker Panels for Detecting Bladder Cancer in a Multi-center Study

Abstract

Purpose: Urothelial bladder cancer presents high recurrence rates, mandating continuous monitoring via invasive cystoscopy. The development of noninvasive tests for disease diagnosis and surveillance remains an unmet clinical need. In this study, validation of two urine-based biomarker panels for detecting primary and recurrent urothelial bladder cancer was conducted.Experimental Design: Two studies (total n ¼ 1,357) were performed for detecting primary (n ¼ 721) and relapsed urothelial bladder cancer (n ¼ 636). Cystoscopy was applied for detecting urothelial bladder cancer, while patients negative for recurrence had follow-up for at least one year to exclude presence of an undetected tumor at the time of sampling. Capillary electrophoresis coupled to mass spectrometry (CE-MS) was employed for the identification of urinary peptide biomarkers. The candidate urine-based peptide biomarker panels were derived from nested cross-sectional studies in primary (n ¼ 451) and recurrent (n ¼ 425) urothelial bladder cancer.Results: Two biomarker panels were developed on the basis of 116 and 106 peptide biomarkers using support vector machine algorithms. Validation of the urine-based biomarker panels in independent validation sets, resulted in AUC values of 0.87 and 0.75 for detecting primary (n ¼ 270) and recurrent urothelial bladder cancer (n ¼ 211), respectively. At the optimal threshold, the classifier for detecting primary urothelial bladder cancer exhibited 91% sensitivity and 68% specificity, while the classifier for recurrence demonstrated 87% sensitivity and 51% specificity. Particularly for patients undergoing surveillance, improved performance was achieved when combining the urine-based panel with cytology (AUC ¼ 0.87).Conclusions: The developed urine-based peptide biomarker panel for detecting primary urothelial bladder cancer exhibits good performance. Combination of the urine-based panel and cytology resulted in improved performance for detecting disease recurrence.

Recent advances in capillary electrophoresis‐mass spectrometry: Instrumentation, methodology and applications

“…reported possible peptide biomarkers to distinguish between pancreatic cancer and chronic pancreatitis in urine . Other applications in cancer research include genitourinary and bladder cancer . Belczacka et al.…”

Proteomics biomarkers for solid tumors: Current status and future prospects

“…Independent validation in respective cohorts resulted in AUC values of 0.87 and 0.75, respectively . Peptide fragments from various collagen chains, APOA1, fibrinogen alpha chain (FGA) and beta‐2‐microglobulin (B2M) were found to be increased in their urinary abundance in the BCa patients, while those of basement membrane‐specific heparan sulfate proteoglycan (HSPG2) and histidine‐rich glycoprotein (HRG) peptides were found to be decreased …”

Selection of small plasma peptides for the auxiliary diagnosis and prognosis of epithelial ovarian cancer by using UPLC/MS‐based nontargeted and targeted analyses

“…Small peptides have normally been defined as the breakdown products of proteins during catalytic events with a comparable size to small molecular metabolites (MW < 1,500 Da), putting them in a gap between the metabolome and the proteome . In fact, in spite of being rarely studied, small peptides such as dipeptides and tripeptides have been of increasing focus in recent years because of their potentials to be biomarkers in clinical diagnosis . However, although the biomarker discovery for EOC diagnosis has been widely conducted by metabolomics and proteomics studies, little effort has been made in the field of specific investigation towards the small peptide metabolic profiles for differentiating EOC patients from patients with similar symptoms.…”