Proteomics

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Liquid biopsy protein biomarkers of cholangiocarcinoma risk, early diagnosis and survival mirroring tumor cells - timsTOF (1/2)


ABSTRACT: Background & Aims: Cholangiocarcinomas (CCAs), heterogeneous biliary tumors with dismal prognosis, lack accurate early-diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods: EVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=42), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (n=34) and healthy individuals (n=55) were characterized by mass-spectrometry. Diagnostic biomarkers of PSC-CCA, non-PSC CCA or CCAs regardless etiology (pan-CCAs) were defined, and their expression was evaluated in human organs/tissues and within CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated. Results: High-throughput proteomics identified candidate diagnostic biomarkers for PSC-CCA, non-PSC CCA or pan-CCA, as well as and for differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning logit modelling disclosed CRP/FRIL/Fibrinogen algorithm with diagnostic value for early-stage PSC-CCA vs isolated PSC (AUC=0.944; OR=82.0), overpowering CA19-9 (AUC=0.735; OR=9.3). An algorithm combining CRP/VWF/PIGR/ /Fibrinogen allowed the diagnosis of early-stage non-PSC CCAs compared to healthy individuals (AUC=0.999; OR=1115). Noteworthy, levels of Fibrinogen/CRP/PIGR/FRIL showed predictive capacity for CCA development in patients with PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EVprognostic biomarkers independent to clinical features, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively. Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA, representing a novel tumor cell-derived liquid biopsy for personalized medicine.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Primary Sclerosing Cholangitis,Cholangiocarcinoma

SUBMITTER: Mikel Azkargorta  

LAB HEAD: Felix Elortza

PROVIDER: PXD036943 | Pride | 2023-07-20

REPOSITORIES: Pride

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Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma.

Lapitz Ainhoa A   Azkargorta Mikel M   Milkiewicz Piotr P   Olaizola Paula P   Zhuravleva Ekaterina E   Grimsrud Marit M MM   Schramm Christoph C   Arbelaiz Ander A   O'Rourke Colm J CJ   La Casta Adelaida A   Milkiewicz Malgorzata M   Pastor Tania T   Vesterhus Mette M   Jimenez-Agüero Raul R   Dill Michael T MT   Lamarca Angela A   Valle Juan W JW   Macias Rocio I R RIR   Izquierdo-Sanchez Laura L   Pérez Castaño Ylenia Y   Caballero-Camino Francisco Javier FJ   Riaño Ioana I   Krawczyk Marcin M   Ibarra Cesar C   Bustamante Javier J   Nova-Camacho Luiz M LM   Falcon-Perez Juan M JM   Elortza Felix F   Perugorria Maria J MJ   Andersen Jesper B JB   Bujanda Luis L   Karlsen Tom H TH   Folseraas Trine T   Rodrigues Pedro M PM   Banales Jesus M JM  

Journal of hepatology 20230301 1


<h4>Background & aims</h4>Cholangiocarcinoma (CCA), heterogeneous biliary tumours with dismal prognosis, lacks accurate early diagnostic methods especially important for individuals at high-risk (i.e. those with primary sclerosing cholangitis [PSC]). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs).<h4>Methods</h4>EVs from patients with isolated PSC (n = 45), concomitant PSC-CCA (n = 44), PSC who developed CCA during follow-up (PSC to CCA; n = 25), CCAs from non-PSC  ...[more]

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