Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway

Goeppert, Benjamin; Konermann, Carolin; Schmidt, Christopher R.; Bogatyrova, Olga; Geiselhart, Lea; Ernst, Christina; Gu, Lei; Becker, Natália; Zucknick, Manuela; Mehrabi, Arianeb; Hafezi, Mohammadreza; Klauschen, Frederick; Stenzinger, Albrecht; Warth, Arne; Breuhahn, Kai; Renner, Marcus; Weichert, Wilko; Schirmacher, Peter; Plass, Christoph; Weichenhan, Dieter

doi:10.1002/hep.26721

Cited by 100 publications

(111 citation statements)

References 38 publications

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“…A retrospective multicentre study published in 2013, including close to 200 patients with iCCA, concluded that intraarterial therapy was safe and this approach resulted in stable disease (62%) or partial to complete response (26%) 253 . The majority of patients were treated with conventional TACE or 90 Y-TARE, and there was no statistically significant difference in overall survival (median 13.2 months) between these two groups. In addition, 90 Y-TARE has provided partial response (27%) or stable disease (68%) in patients with iCCA 254 .…”

Section: Locoregional Therapymentioning

confidence: 93%

“…The majority of patients were treated with conventional TACE or 90 Y-TARE, and there was no statistically significant difference in overall survival (median 13.2 months) between these two groups. In addition, 90 Y-TARE has provided partial response (27%) or stable disease (68%) in patients with iCCA 254 . Hepatic arterial infusion includes a catheter-based intra-arterial infusion of chemotherapeutic agents, without embolization 253 .…”

Section: Locoregional Therapymentioning

confidence: 93%

“…Marked reduction in DNA hydroxymethylation character izes CCA tissue when compared with non-neoplastic tissue and a DNA mCyt content of ≥5.59% in peripheral blood mononuclear cells relates to a favourable outcome in primary liver cancers 81 . On the other hand, several promoters of genes involved in Wnt signalling are hypermethylated in CCA tissue 90 . A number of publications strongly suggest that epi genetic changes are early events in the malignant process, linking the tumour epigenetics to the microenvironment 82 and opening up opportunities for early detection of CCA 83 .…”

Section: Epigenetic Modificationsmentioning

confidence: 99%

See 2 more Smart Citations

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Bañales

Cardinale

Carpino

et al. 2016

Nat Rev Gastroenterol Hepatol

1,105

1,139

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Section: Locoregional Therapymentioning

confidence: 93%

Section: Locoregional Therapymentioning

confidence: 93%

Section: Epigenetic Modificationsmentioning

confidence: 99%

See 1 more Smart Citation

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Bañales

Cardinale

Carpino

et al. 2016

Nat Rev Gastroenterol Hepatol

1,105

1,139

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“…2) WNT signaling. The WNT pathway is highly activated in the tumor epithelium of human CCAs and is often characterized by overexpression of the ligands WNT7B and WNT10A along with several target genes (69,70). It has been demonstrated that inflammatory macrophages in the stroma surrounding the tumor are required for the maintenance of this highly activated WNT signaling status (69,71).…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

Moeini

Sia

Bardeesy

et al. 2016

Clinical Cancer Research

205

176

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Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA-and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatinremodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarkerdriven trials are currently underway.

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“…Intriguingly, the etiological origins of CCA have been shown to impact on the associated mutational landscapes, both in comparisons of liver fluke-associated and non-associated tumors [34] , as well as hepatitis-positive versus -negative tumors [35] . Epigenetic lesions, such as focal promoter-associated hypermethylation [36,37] , global loss of 5-hydroxymethylcytosine [38] and aberrant non-coding RNA expression [39,40] , also contribute to iCCA pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

Høgdall

O’Rourke

Taranta

et al. 2016

Dig Dis

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Intrahepatic cholangiocarcinoma (iCCA) comprises one of the most rapidly evolving cancer types. An underlying chronic inflammatory liver disease that precedes liver cancer development for several decades and creates a pro-oncogenic microenvironment frequently impairs progress in therapeutic approaches. Depending on the cellular target of malignant transformation, a large spectrum of molecular and morphological patterns is observed. As such, it is crucial to advance our existing understanding of the molecular pathogenesis of iCCA, particularly its genomic heterogeneity, to improve current clinical strategies and patient outcome. This was achieved for other cancers, such as breast carcinoma, facilitated by the delineation of patient subsets and of precision therapies. In iCCA, many questions persevere as to the evolutionary process and cellular origin of the initial transforming event, the context of tumor plasticity and the causative features driving the disease. Molecular profiling and pathological techniques have begun to underline persistent alterations that may trigger inherited drug resistance (a hallmark of hepatobiliary and pancreatic cancers), metastasis and disease recurrence. In this review, we will focus on the key molecular achievements that are currently advancing the characterization and stratification of iCCA. We will discuss current clinical practice and how genomic achievements may advance diagnosis and therapy as well as ultimately improve patient outcome.

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Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway

Cited by 100 publications

References 38 publications

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

Molecular Pathogenesis and Current Therapy in Intrahepatic Cholangiocarcinoma

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