Urine proteomic analysis differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders
- Jochen Metzger1,
- Ahmed A Negm2,
- Ruben R Plentz3,
- Tobias J Weismüller2,4,
- Jochen Wedemeyer5,
- Tom H Karlsen6,
- Mohammed Dakna1,
- William Mullen7,
- Harald Mischak1,7,
- Michael P Manns2,4,
- Tim O Lankisch2,4
- 1Mosaiques diagnostics GmbH, Hannover, Germany
- 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- 3Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany
- 4Integrated Research and Treatment Center - Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
- 5Department of Internal Medicine, Robert Koch Hospital, Gehrden, Germany
- 6Norwegian PSC Research Center, Clinic for Specialized Surgery and Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- 7BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
- Correspondence to Dr Tim Oliver Lankisch, Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany;
Contributors JM and TOL designed the experiments and wrote the manuscript; AAN, TJW, THK and TOL performed patient diagnosis, patient enrolment and collection of clinical data; JM, RRP and WM performed the experimental work; JW, HM, MD and MPM supervised the experiments and their analysis.
- Revised 10 April 2012
- Accepted 11 April 2012
- Published Online First 12 May 2012
Background Diagnosis and curative treatment of cholangiocarcinoma (CC) often comes too late due to the lack of reliable tumour markers especially in patients with primary sclerosing cholangitis (PSC). The authors recently introduced bile proteomic analysis for CC diagnosis. Nevertheless, bile collection depends on invasive endoscopic retrograde cholangiography. The authors therefore evaluated urine proteomic analysis for non-invasive CC diagnosis.
Methods Using capillary electrophoresis mass spectrometry the authors established a CC-specific peptide marker model based on the distribution of 42 peptides in 14 CC, 13 PSC and 14 benign biliary disorder (BBD) patients.
Results In cross-sectional validation of 123 patients, the urine peptide marker model correctly classified 35 of 42 CC patients and 64 of 81 PSC and BBD patients with an area under the curve value of 0.87 (95% CI 0.80 to 0.92, p=0.0001, 83% sensitivity, 79% specificity). Evaluation of 101 normal controls resulted in 86% specificity. All 10 patients with CC on top of PSC were correctly classified. The majority of sequence-identified peptides are fragments of interstitial collagens with some of them also detected in blood indicating their extra-renal origin. Immunostaining of liver sections for matrix metallopeptidase 1 indicated increased activity of the interstitial collagenase in liver epithelial cells of CC patients.
Conclusion The urine test differentiates CC from PSC and other BBD and may provide a new diagnostic non-invasive tool for PSC surveillance and CC detection.
- Biliary stricture
- urine proteomic analysis
- PSC surveillance
- pancreatic cancer
- hepatocellular carcinoma
- biliary endoscopy
Funding This work was supported by the Niedersächsischen Krebsgesellschaft and a grant from the German Federal Ministry of Education and Research (reference number: 01EO0802). JM and HM are supported by grant 260844 from the HEPACUTE EU-project.
Competing interests HM is founder and co-owner of Mosaiques diagnostics, which developed the CE–MS technology and the MosaiquesVisu and MosaCluster software. JM and MD are employees of Mosaiques diagnostics.
Patient consent Obtained.
Ethics approval Ethics approval was provided by the local ethical committees.
Provenance and peer review Not commissioned; externally peer reviewed.