Cholangiokarcinom patří mezi zhoubná nádorová onemocnění s velmi nepříznivou prognózou, pětileté přežití se týká méně než 10 % pacientů. Pokrok v oblasti molekulárních analýz těchto nádorů však velmi rozšířil možnosti cílené léčby. K nejčastěji identifikovaným změnám cholangiokarcinomu patří mutace isocitrátdehydrogenázy 1 (IDH1). Ivosidenib (Tibsovo®) jako cílený inhibitor této enzymatické varianty může nyní uplatnit svoji účinnost.

Patients suffering from cholangiocarcinoma have very unfavorable prognosis, 5 years survival is usually less than 10 %. Progress in molecular testing of this tumors revealed better possibilities of targeted therapy. One of the most represented changes is isocitrate dehydrogenase-1 (IDH-1) mutation. Selective inhibitor of mutated IDH-1 enzyme ivosidenib (Tibsovo®) is effective choice of treatment of this disease.

• Keywords
• ivosidenib,
• MeSH
• Cholangiocarcinoma * diagnosis   drug therapy   genetics   MeSH
• Molecular Targeted Therapy * classification   methods   MeSH
• Isocitrate Dehydrogenase antagonists & inhibitors   genetics   MeSH
• Humans MeSH
• Survival Rate MeSH
• Mutation drug effects   MeSH
• Drug-Related Side Effects and Adverse Reactions classification   MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

• MeSH
• Biopsy MeSH
• Cholangiocarcinoma * diagnosis   genetics   MeSH
• Molecular Diagnostic Techniques MeSH
• Isocitrate Dehydrogenase genetics   MeSH
• Humans MeSH
• Mutation MeSH
• High-Throughput Nucleotide Sequencing methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Overall MeSH

Cholangiocelulární karcinom je poměrně vzácný maligní nádor vycházející z cholangiocytů, se špatnou prognózou a zpravidla pozdně stanovenou diagnózou. Jedná se o malignitu s různorodou biologií a řadou genetických i epigenetických změn. Jeho incidence v ČR činí asi 1,4 případu na 100 000 obyvatel za rok. Pro příznivou prognózu a naději na delší přežití je důležitá časná diagnostika s chirurgickým řešením. V těchto případech dosahuje 5letého přežití asi 20–40 % pacientů. V časné diagnostice hrají zásadní roly zobrazovací metody a histopatologická verifikace; laboratorní onkomarkery zatím nejsou dostatečně vypovídající. Totéž platí také o genetických markerech, což vede k hledání nových molekulárních cílů a zavedení cytologických a molekulárně biologických metod s vysokou specificitou a senzitivitou do rutinní praxe. Současná racionální časná diagnostika spočívá v účelném využití zobrazovacích metod. Využití genetického testování, a hlavně znalost molekulární podstaty tohoto onemocnění bude velkým přínosem. Jako významné se jeví sledování asociace s genetickými dráhami IDH1 a RAS-MAPK a dále sledování genetických mutací genů TP53, KRAS, SMAD4, BRAF, IDH1/2 a dalších. Z molekulárního hlediska nelze podcenit také onkovirový potenciál infekce HBV/HCV.

Cholangiocellular carcinoma is a relatively rare malignant tumor, originating from cholangiocytes, with poor prognosis and late diagnosis. It is a malignancy with a variable biological etiology, numerous genetic and epigenetic changes. Its incidence in the Czech Republic is about 1.4 per 100,000 people per year. For good prognosis and long-term survival, early diagnosis with surgical treatment is important. In these cases, a 5-year survival rate is about 20-40 %. In the early diagnosis imaging methods and histopathological verification play an essential role, whereas laboratory oncomarkers are not yet sufficiently accurate. The same applies for genetic markers. This leads to the search of new molecular targets and the high effort in the introduction of cytological and molecular-biological methods with high specificity and sensitivity into routine practice. Current early diagnosis is based on the use of efficient imaging methods. The use of genetic testing, and especially knowledge of the molecular basis of this disease, will be of a great benefit. The observation of the association between the genetic pathways, IDH1, RAS-MAPK etc., and genetic mutations of genes, such as TP53, KRAS, SMAD4, BRAF, IDH1/2, may be significant. From the molecular point of view, it is also interesting to monitor oncogenic potential in HBV/HCV infection.

• MeSH
• Cholangiocarcinoma * diagnosis   genetics   therapy   MeSH
• Cantharidin therapeutic use   MeSH
• Humans MeSH
• Pathology, Molecular * MeSH
• Mutation genetics   MeSH
• Biomarkers, Tumor MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2-LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556-67. ©2018 AACR.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   MeSH
• Cell Nucleus drug effects   MeSH
• Cholangiocarcinoma drug therapy   genetics   pathology   MeSH
• Cytoplasm drug effects   MeSH
• Dasatinib administration & dosage   MeSH
• Phosphoproteins genetics   MeSH
• Phosphorylation drug effects   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Cell Proliferation drug effects   MeSH
• Protein Serine-Threonine Kinases genetics   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   MeSH
• src-Family Kinases antagonists & inhibitors   genetics   MeSH
• Tyrosine genetics   MeSH
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) genetics   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Myeloblastosis-associated virus 2 (MAV-2) is a highly tumorigenic simple avian retrovirus. Chickens infected in ovo with MAV-2 develop tumors in the kidneys, lungs, and liver with a short latency, less than 8 weeks. Here we report the results of molecular analyses of MAV-2-induced liver tumors that fall into three classes: hepatic hemangiosarcomas (HHSs), intrahepatic cholangiocarcinomas (ICCs), and hepatocellular carcinomas (HCCs). Comprehensive inverse PCR-based screening of 92 chicken liver tumors revealed that in ca. 86% of these tumors, MAV-2 provirus had integrated into one of four gene loci: HRAS, EGFR, MET, and RON Insertionally mutated genes correlated with tumor type: HRAS was hit in HHSs, MET in ICCs, RON mostly in ICCs, and EGFR mostly in HCCs. The provirus insertions led to the overexpression of the affected genes and, in the case of EGFR and RON, also to the truncation of exons encoding the extracellular ligand-binding domains of these transmembrane receptors. The structures of truncated EGFR and RON closely mimic the structures of oncogenic variants of these genes frequently found in human tumors (EGFRvIII and sfRON).IMPORTANCE These data describe the mechanisms of oncogenesis induced in chickens by the MAV-2 retrovirus. They also show that molecular processes converting cellular regulatory genes to cancer genes may be remarkably similar in chickens and humans. We suggest that the MAV-2 retrovirus-based model can complement experiments performed using mouse models and provide data that could translate to human medicine.

• MeSH
• Cholangiocarcinoma genetics   virology   MeSH
• Genes, erbB-1 * MeSH
• Hemangiosarcoma genetics   virology   MeSH
• Carcinoma, Hepatocellular genetics   virology   MeSH
• Virus Integration MeSH
• Mutagenesis, Insertional * MeSH
• Carcinogenesis * MeSH
• Chickens genetics   MeSH
• Humans MeSH
• Liver Neoplasms genetics   virology   MeSH
• Oncogenes MeSH
• Proto-Oncogene Proteins c-met genetics   MeSH
• Proviruses genetics   physiology   MeSH
• Avian Proteins genetics   MeSH
• Receptor Protein-Tyrosine Kinases genetics   MeSH
• Avian Myeloblastosis Virus genetics   physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Cholangiokarcinom (CC) je vzácný maligní nádor vznikající z cholangiocytů. Prognóza CC bývá většinou nepříznivá. Zásadní podíl na této skutečnosti má pozdní diagnóza nádoru. Současná incidence CC v České republice činí asi 1,4 na 100 000 obyvatel za rok; u méně než 30 % pacientů s CC lze identifikovat některý ze známých rizikových faktorů, nejčastěji primární sklerozující cholangiitidu. Naději na delší dobu přežití mají pacienti s časně diagnostikovaným, chirurgicky řešitelným CC, u kterých dosahuje 5letá doba přežití asi 20–40 %. Pro časnou diagnózu CC mají zásadní význam zobrazovací metody a histopatologické zhodnocení, zatímco časně diagnostický význam onkomarkerů je omezený. Racionální časná diagnostika CC spočívá v účelném využití diferencovaných výhod jednotlivých zobrazovacích metod – optimální se jeví MRI s DSA, EUS je citlivou metodou pro identifikaci malignit v oblasti jaterního hilu nebo distálního choledochu, zatímco MRCP (magnetic resonance cholangiopancreatography) spíše při zobrazení patologických změn biliárního stromu, ERCP (endoscopic retrograde cholangiopancreatography) umožňuje odběr materiálu pro histopatologické vyšetření. Přínosem jsou i novější diagnostické metody, např. IDUS – intraduktální ultrasonografie biliárních cest anebo SPY-GLASS, umožňující vyšetřit žlučové cesty přímým pohledem s možností odběru cíleného bioptického vzorku. Specificitu i senzitivitu histologického a cytologického vyšetření lze zvýšit využitím molekulárně cytogenetické metody FISH, tj. fluorescenční in situ hybridizací, u níž specificita dosahuje 97 %.

Cholangiocarcinoma (CC) is a rare malignant tumour arising from cholangiocytes, and its prognosis is usually unfavourable, mostly as a result of late diagnosis of the tumour. The current incidence of cholangiocarcinoma in the Czech Republic is 1.4/100,000 inhabitants per year; in less than 30 % of patients with CC, one of the known risk factors can be identified, most frequently, primary sclerosing cholangitis. Only patients with early diagnosed and surgically amenable cholangiocarcinoma are likely to have a longer survival time; in their case, survival for more than five years has been achieved in 20 % to 40 %. From the perspective of the need for early diagnosis of CC, a significant part is played by imaging and histopathologic evaluation; the early diagnostic significance of oncomarkers is limited. The rational early diagnosis of CC consists in effective use of differentiated advantages of different imaging modalities – MRI with DSA appears to be the optimal method, endosonography is a sensitive method for the identification of malignancy in the hepatic hilum or distal common bile duct, MRCP (magnetic resonance cholangiopancreatography) is used to display pathological changes in the biliary tree, ERCP (endoscopic retrograde cholangiopancreatography) allows material removal for histopathological examination. Other new approaches are also beneficial, such as IDUS – intraductal ultrasonography of biliary tract or SPY-GLASS, enabling examination of the bile ducts by direct view with the possibility of taking targeted biopsies. Sensitivity and specificity of histology and cytology can be increased by using the molecular cytogenetic FISH method, i.e. fluorescence in situ by hybridization, with a specificity of 97 %.

• MeSH
• Endoscopic Ultrasound-Guided Fine Needle Aspiration MeSH
• Early Detection of Cancer methods   MeSH
• Cholangiocarcinoma * diagnosis   genetics   classification   pathology   MeSH
• Cholangiopancreatography, Endoscopic Retrograde * MeSH
• Common Bile Duct anatomy & histology   MeSH
• Endosonography * methods   MeSH
• Immunohistochemistry MeSH
• Humans MeSH
• Cholangiopancreatography, Magnetic Resonance MeSH
• Prognosis MeSH
• Risk Factors MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulfide isomerases. Since there is little information on how AGR3 is expressed in normal and diseased tissues and what its exact function is, we analyzed its expression pattern in normal liver and tumor tissue of ICC and HCC. The immunohistochemical analysis in normal tissue revealed specific AGR3 expression in intrahepatic bile duct cholangiocytes which was not present in liver hepatocytes. Consequently we analyzed AGR3 expression in 74 representative samples of puncture biopsies, tissue excisions and resection specimens from which 48 samples were diagnosed as HCC and 26 as ICC. Our results showed AGR3 expression negative and weakly positive respectively in hepatocellular carcinomas compared to stronger AGR3 positivity in cholangiocellular carcinomas. AGR3 expression statistically significantly correlated to acid mucopolysaccharide expression and negatively correlated to glypican-3 expression. We conclude that according to receiver operating characteristics (ROC) analysis AGR3 expression is relatively specific for ICC and is potentially linked to mucosecretion, which may indicate potential implication in treatment resistance.

• MeSH
• Cholangiocarcinoma diagnosis   genetics   MeSH
• Diagnosis, Differential MeSH
• Adult MeSH
• Genetic Markers MeSH
• Glypicans genetics   metabolism   MeSH
• Carcinoma, Hepatocellular diagnosis   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   metabolism   MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Liver Neoplasms diagnosis   genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Carrier Proteins genetics   metabolism   MeSH
• Bile Ducts, Intrahepatic metabolism   pathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH