Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma
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 (E...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/155299 |
| Acceso en línea: | http://hdl.handle.net/10366/155299 |
| Access Level: | acceso abierto |
| Palabra clave: | cholangiocarcinoma biomarker Liver Neoplasms Early Diagnosis Cholangiocarcinoma Cholangitis Carcinoma Humans Bile Ducts Carbohydrates Bile Duct Neoplasms Nuclear Proteins 3209 Farmacología diagnóstico precoz conductos biliares neoplasias hepáticas neoplasias de los conductos biliares humanos carcinoma colangiocarcinoma colangitis hidratos de carbono proteínas nucleares |
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| dc.title.none.fl_str_mv |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| title |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| spellingShingle |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma Lapitz, Ainhoa cholangiocarcinoma biomarker Liver Neoplasms Early Diagnosis Cholangiocarcinoma Cholangitis Carcinoma Humans Bile Ducts Carbohydrates Bile Duct Neoplasms Nuclear Proteins 3209 Farmacología diagnóstico precoz conductos biliares neoplasias hepáticas neoplasias de los conductos biliares humanos carcinoma colangiocarcinoma colangitis hidratos de carbono proteínas nucleares |
| title_short |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| title_full |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| title_fullStr |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| title_full_unstemmed |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| title_sort |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinoma |
| dc.creator.none.fl_str_mv |
Lapitz, Ainhoa Azkargorta, Mikel Milkiewicz, Piotr Olaizola, Paula Zhuravleva, Ekaterina Grimsrud, Marit M Schramm, Christoph Arbelaiz, Ander O'Rourke, Colm J La Casta, Adelaida Milkiewicz, Malgorzata Pastor, Tania Vesterhus, Mette Jimenez-Agüero, Raul Dill, Michael T Lamarca, Angela Valle, Juan W Rodríguez Macías, Rocío Isabel Izquierdo-Sanchez, Laura Pérez Castaño, Ylenia Caballero-Camino, Francisco Javier Riaño, Ioana Krawczyk, Marcin Ibarra, Cesar Bustamante, Javier Nova-Camacho, Luiz M Falcon-Perez, Juan M Elortza, Felix Perugorria, Maria J Andersen, Jesper B Bujanda, Luis Karlsen, Tom H Folseraas, Trine Rodrigues, Pedro M Banales, Jesus M. |
| author |
Lapitz, Ainhoa |
| author_facet |
Lapitz, Ainhoa Azkargorta, Mikel Milkiewicz, Piotr Olaizola, Paula Zhuravleva, Ekaterina Grimsrud, Marit M Schramm, Christoph Arbelaiz, Ander O'Rourke, Colm J La Casta, Adelaida Milkiewicz, Malgorzata Pastor, Tania Vesterhus, Mette Jimenez-Agüero, Raul Dill, Michael T Lamarca, Angela Valle, Juan W Rodríguez Macías, Rocío Isabel Izquierdo-Sanchez, Laura Pérez Castaño, Ylenia Caballero-Camino, Francisco Javier Riaño, Ioana Krawczyk, Marcin Ibarra, Cesar Bustamante, Javier Nova-Camacho, Luiz M Falcon-Perez, Juan M Elortza, Felix Perugorria, Maria J Andersen, Jesper B Bujanda, Luis Karlsen, Tom H Folseraas, Trine Rodrigues, Pedro M Banales, Jesus M. |
| author_role |
author |
| author2 |
Azkargorta, Mikel Milkiewicz, Piotr Olaizola, Paula Zhuravleva, Ekaterina Grimsrud, Marit M Schramm, Christoph Arbelaiz, Ander O'Rourke, Colm J La Casta, Adelaida Milkiewicz, Malgorzata Pastor, Tania Vesterhus, Mette Jimenez-Agüero, Raul Dill, Michael T Lamarca, Angela Valle, Juan W Rodríguez Macías, Rocío Isabel Izquierdo-Sanchez, Laura Pérez Castaño, Ylenia Caballero-Camino, Francisco Javier Riaño, Ioana Krawczyk, Marcin Ibarra, Cesar Bustamante, Javier Nova-Camacho, Luiz M Falcon-Perez, Juan M Elortza, Felix Perugorria, Maria J Andersen, Jesper B Bujanda, Luis Karlsen, Tom H Folseraas, Trine Rodrigues, Pedro M Banales, Jesus M. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
cholangiocarcinoma biomarker Liver Neoplasms Early Diagnosis Cholangiocarcinoma Cholangitis Carcinoma Humans Bile Ducts Carbohydrates Bile Duct Neoplasms Nuclear Proteins 3209 Farmacología diagnóstico precoz conductos biliares neoplasias hepáticas neoplasias de los conductos biliares humanos carcinoma colangiocarcinoma colangitis hidratos de carbono proteínas nucleares |
| topic |
cholangiocarcinoma biomarker Liver Neoplasms Early Diagnosis Cholangiocarcinoma Cholangitis Carcinoma Humans Bile Ducts Carbohydrates Bile Duct Neoplasms Nuclear Proteins 3209 Farmacología diagnóstico precoz conductos biliares neoplasias hepáticas neoplasias de los conductos biliares humanos carcinoma colangiocarcinoma colangitis hidratos de carbono proteínas nucleares |
| description |
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). 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 aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients' survival, respectively. Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine. The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2024 2024 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10366/155299 |
| url |
http://hdl.handle.net/10366/155299 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
PI20/00189 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
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reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca instname:Universidad de Salamanca (USAL) |
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Universidad de Salamanca (USAL) |
| reponame_str |
GREDOS. Repositorio Institucional de la Universidad de Salamanca |
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GREDOS. Repositorio Institucional de la Universidad de Salamanca |
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| _version_ |
1869410859607916544 |
| spelling |
Liquid biopsy-based protein biomarkers for risk prediction, early diagnosis, and prognostication of cholangiocarcinomaLapitz, AinhoaAzkargorta, MikelMilkiewicz, PiotrOlaizola, PaulaZhuravleva, EkaterinaGrimsrud, Marit MSchramm, ChristophArbelaiz, AnderO'Rourke, Colm JLa Casta, AdelaidaMilkiewicz, MalgorzataPastor, TaniaVesterhus, MetteJimenez-Agüero, RaulDill, Michael TLamarca, AngelaValle, Juan WRodríguez Macías, Rocío IsabelIzquierdo-Sanchez, LauraPérez Castaño, YleniaCaballero-Camino, Francisco JavierRiaño, IoanaKrawczyk, MarcinIbarra, CesarBustamante, JavierNova-Camacho, Luiz MFalcon-Perez, Juan MElortza, FelixPerugorria, Maria JAndersen, Jesper BBujanda, LuisKarlsen, Tom HFolseraas, TrineRodrigues, Pedro MBanales, Jesus M.cholangiocarcinomabiomarkerLiver NeoplasmsEarly DiagnosisCholangiocarcinomaCholangitisCarcinomaHumansBile DuctsCarbohydratesBile Duct NeoplasmsNuclear Proteins3209 Farmacologíadiagnóstico precozconductos biliaresneoplasias hepáticasneoplasias de los conductos biliareshumanoscarcinomacolangiocarcinomacolangitishidratos de carbonoproteínas nuclearesCholangiocarcinoma (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). 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 aetiology (n = 56), and hepatocellular carcinoma (n = 34) and healthy individuals (n = 56) were characterised by mass spectrometry. Diagnostic biomarkers for PSC-CCA, non-PSC CCA, or CCAs regardless of aetiology (Pan-CCAs) were defined and validated by ELISA. Their expression was evaluated in CCA tumours at a single-cell level. Prognostic EV biomarkers for CCA were investigated. High-throughput proteomics of EVs identified diagnostic biomarkers for PSC-CCA, non-PSC CCA, or Pan-CCA, and for the differential diagnosis of intrahepatic CCA and hepatocellular carcinoma, which were cross-validated by ELISA using total serum. Machine learning-based algorithms disclosed CRP/FIBRINOGEN/FRIL for the diagnosis of PSC-CCA (local disease [LD]) vs. isolated PSC (AUC = 0.947; odds ratio [OR] =36.9) and, combined with carbohydrate antigen 19-9, overpowers carbohydrate antigen 19-9 alone. CRP/PIGR/VWF allowed the diagnosis of LD non-PSC CCAs vs. healthy individuals (AUC = 0.992; OR = 387.5). It is noteworthy that CRP/FRIL accurately diagnosed LD Pan-CCA (AUC = 0.941; OR = 89.4). Levels of CRP/FIBRINOGEN/FRIL/PIGR showed predictive capacity for CCA development in PSC before clinical evidence of malignancy. Multi-organ transcriptomic analysis revealed that serum EV biomarkers were mostly expressed in hepatobiliary tissues, and single-cell RNA sequencing and immunofluorescence analysis of CCA tumours showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EV prognostic biomarkers, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively and positively with patients' survival, respectively. Serum EVs contain protein biomarkers for the prediction, early diagnosis, and prognostication of CCA that are detectable using total serum, representing a tumour cell-derived liquid biopsy tool for personalised medicine. The accuracy of current imaging tests and circulating tumour biomarkers for cholangiocarcinoma (CCA) diagnosis is far from satisfactory. Most CCAs are considered sporadic, although up to 20% of patients with primary sclerosing cholangitis (PSC) develop CCA during their lifetime, constituting a major cause of PSC-related death. This international study has proposed protein-based and aetiology-related logistic models with predictive, diagnostic, or prognostic capacities by combining two to four circulating protein biomarkers, moving a step forward into personalised medicine. These novel liquid biopsy tools may allow the (i) easy and non-invasive diagnosis of sporadic CCAs, (ii) identification of patients with PSC with higher risk for CCA development, (iii) establishment of cost-effective surveillance programmes for the early detection of CCA in high-risk populations (e.g. PSC), and (iv) prognostic stratification of patients with CCA, which, altogether, may increase the number of cases eligible for potentially curative options or to receive more successful treatments, decreasing CCA-related mortality.Spanish Carlos III Health Institute (ISCIII)202420242023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10366/155299reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésPI20/00189info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1552992026-06-07T06:28:51Z |
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15,300719 |