Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma

Montal, Robert; Sia, Daniela; Montironi, Carla; Leow, Wei Qiang; Esteban-Fabró, Roger; Pinyol, Roser; Torres‐Martín, Miguel; Bassaganyas, Laia; Moeini, Agrin; Peix, Judit; Cabellos, Laia; Maeda, Miho; Villacorta‐Martin, Carlos; Tabrizian, Parissa; Rodríguez‐Carunchio, Leonardo; Castellano, Giancarlo; Sempoux, Christine; Mínguez, Beatriz; Pawlik, Timothy M.; Labgaa, Ismaïl; Roberts, Lewis R.; Solé, Manel; Fiel, M. Isabel; Thung, Swan N.; Fuster, Josep; Roayaie, Sasan; Villanueva, Augusto; Schwartz, M.; Llovet, Josep M.

doi:10.1016/j.jhep.2020.03.008

Cited by 206 publications

(198 citation statements)

References 67 publications

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“…Datasets of cholangiocarcinoma from GEO were searched, and the selection criteria were set as cholangiocarcinoma, Homo species and extrahepatic cancer. The GSE132305 dataset was the newest one, with microarray data from 182 extrahepatic cholangiocarcinomas 44 . The raw data were downloaded and analysed for the expression of SFRP1 mRNA.…”

Section: Methodsmentioning

confidence: 99%

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

Chao

Overman

et al. 2020

Sci Rep

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Ampullary adenocarcinoma is a rare gastrointestinal cancer in which WNT signalling dysregulation has been previously reported. Secreted frizzled related protein 1 (SFRP1) is one of the extracellular ligands of WNT signalling. We performed bioinformatics analyses of SFRP1 expression in human cancer. Microarray analysis of SFRP1 in periampullary adenocarcinoma was obtained from the Gene Expression Omnibus GSE39409 dataset. SFRP1 expression in ampullary adenocarcinoma was detected by immunohistochemistry staining and correlated with patients' clinical outcomes. Our results showed that SFRP1 expression had different clinical applications in all types of human cancer. no detected alteration of SFPR1 gene and SFRP1 expression in ampullary adenocarcinoma was lower than that in other periampullary adenocarcinomas. However, high expression levels of SFRP1 protein were correlated with cancer recurrence, peritoneal carcinomatosis and poor patient prognosis. Gene set enrichment analysis showed downregulation of multiple WNT-related genes in primary culture cells from ampullary adenocarcinoma, but SFRP1 expression was increased. We found an interaction between WNT, bone morphogenetic protein and hedgehog signalling with SFRP1. Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients. Because it is a multifunctional protein, SFRP1 targeting serves as a potential therapy for ampullary adenocarcinoma patients.

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Section: Methodsmentioning

confidence: 99%

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

Chao

Overman

et al. 2020

Sci Rep

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“…Further, expression of programmed death ligand 1 (PD-L1) has been analyzed, and its recurrent expression has been observed in multiple cohorts of iCCA and eCCA [46,47]. However, immune cells seem to express more PD-L1 than cancer cells [46,[48][49][50][51], and PD-L1 expression on tumor cells correlates with a lower response to immunotherapy [52].…”

Section: T and B Cells In Ccamentioning

confidence: 99%

“…Based on the transcriptomic data, the authors classified 189 eCCA into four subgroups depending on the genes that were expressed: the metabolic, proliferating, mesenchymal, and immune group. Moreover, they identified 25% of tumors with actionable genomic alterations, which could be potentially targeted in a therapeutic setting [50].…”

Section: Molecular Characterization Of Ccamentioning

confidence: 99%

Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

Malenica

Donadon

Lleo

2020

Cancers

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Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community.

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“…The profile of PTEN overexpression in CCA also has been checked by transcriptome array (GSE146196). A study classified their molecular panels and re-evaluated four classes for eCCA (KRAS: 36.7%, TP53:34.7%, ARID1A: 14% and SMAD4:10.7%) (GSE132305) [ 92 ]. All GSE datasets have been rationally designed, with appropriate criteria and comprehensively analyzed.…”

Section: Available Omics Datasets For Ccamentioning

confidence: 99%

Omics-Based Platforms: Current Status and Potential Use for Cholangiocarcinoma

et al. 2020

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Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer that can be transformed from epithelial cells of the bile duct, including intrahepatic, perihilar and extrahepatic. High-resolution imaging tools (abdominal ultrasound, computed tomography and percutaneous transhepatic cholangial drainage) are recruited for diagnosis. However, the lack of early diagnostic biomarkers and treatment evaluation can lead to serious outcomes and poor prognosis (i.e., CA19-9, MUC5AC). In recent years, scientists have established a large number of omics profiles to reveal underlying mechanisms and networks (i.e., IL-6/STAT3, NOTCH). With these results, we achieved several genomic alteration events (i.e., TP53mut, KRASmut) and epigenetic modifications (i.e., DNA methylation, histone modification) in CCA cells and clinical patients. Moreover, we reviewed candidate gene (such as NF-kB, YAP1) that drive gene transcription factors and canonical pathways through transcriptomics profiles (including microarrays and next-generation sequencing). In addition, the proteomics database also indicates which molecules and their directly binding status could trigger dysfunction signatures in tumorigenesis (carbohydrate antigen 19-9, mucins). Most importantly, we collected metabolomics datasets and pivotal metabolites. These results reflect the pharmacotherapeutic options and evaluate pharmacokinetic/pharmacodynamics in vitro and in vivo. We reversed the panels and selected many potentially small compounds from the connectivity map and L1000CDS2 system. In this paper, we summarize the prognostic value of each candidate gene and correlate this information with clinical events in CCA. This review can serve as a reference for further research to clearly investigate the complex characteristics of CCA, which may lead to better prognosis, drug repurposing and treatment strategies.

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Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma

Cited by 206 publications

References 67 publications

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence

Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

Omics-Based Platforms: Current Status and Potential Use for Cholangiocarcinoma

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