Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma

Nepal, Chirag; O’Rourke, Colm J.; Oliveira, Douglas V.N.P.; Taranta, Andrzej; Shema, Steven; Gautam, Prson; Caldéraro, Julien; Barbour, Andrew P.; Raggi, Chiara; Wennerberg, Krister; Wang, Xin Wei; Lautem, Anja; Roberts, Lewis R.; Andersen, Jesper B.

doi:10.1002/hep.29764

Cited by 104 publications

(120 citation statements)

References 47 publications

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“…We found that ARID1A was predominantly mutated in eCCA, which is in discrepancy with data earlier reported ; however, this may be due to our relatively small cohort. ARID1A aberrations were found in 33% which has previously been reported with lower frequencies by Nepal et al (9.9%) and Wardell et al (6%) but closer by Nakamura et al (17%) , Jiao et al (19%) and in our database reference, likely reflective of heterogeneous patient populations (Table ). TP53 was found mutated in 33% of the cases as compared to our reference (21%) but in accordance with Nakamura et al both in overall frequency (33.9%) and with a slight predominance in eCCA .…”

Section: Discussionsupporting

confidence: 76%

“…Stringent analysis and data reporting as a standard for all BTC patients will increase our knowledge in individual demographic and etiological groups, but may be challenging in daily routines. However, exome sequencing is implemented for colorectal cancer patients at Herlev and Gentofte Hospital and utilizing the same procedures may be an attractive path to increase our knowledge of BTC and subsequently provide novel knowledge based on pooled analysis in this rare disease . Here, we report mutational data from exome sequencing of 22 genes using tissue from diagnostic biopsies collected through an earlier reported phase 2 trial investigating the efficacy of gemcitabine, capecitabine, and oxaliplatin with or without cetuximab in patients with BTC .…”

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confidence: 99%

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Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

Høgdall

Larsen

Linnemann

et al. 2019

APMIS

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Biliary tract cancers (BTC) are a rare heterogeneous disease group with a dismal prognosis and limited treatment options. The mutational landscape consists of genetic aberrations both shared by and characteristic for anatomical location. Here, we present exome sequencing data on 22 genes from a phase 2 trial using a clinically validated panel used in patients with colorectal cancer. A total of 56 patients were included in a one‐armed phase 2 trial investigating the treatment combination of capecitabine, gemcitabine, oxaliplatin, and cetuximab. Tissue DNA yield and quality allowed analysis of 30 patients on our panel including 22 genes. ARID1A (33%) and TP53 (33%) were found to be most frequently mutated followed by KRAS mutations found in 20% of the patients. Mutational aberrations in ARID1A were found more prevalent than expected, whereas TP53 and KRAS were in concordance with earlier reported data. Mutation in CTNNB1 was significantly associated with poor prognosis. Our panel is clinically validated and suitable for a high volume of samples to detect mutations in patients with BTC. However, it is reasonable to assume that the clinical utility could be optimized in this patient group by extending the panel to include BTC specific mutations with potential therapeutic consequences such as IDH1/2, FGFR fusions, ERBB3, and BRCA1/2.

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Section: Discussionsupporting

confidence: 76%

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confidence: 99%

Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

Høgdall

Larsen

Linnemann

et al. 2019

APMIS

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“…Cholangiocarcinoma accounts for approximately 10% of primary hepatic tumors and is divided into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) [1,2]. Nearly 80%-90% of cholangiocarcinomas are of extrahepatic origin and are divided into perihilar (Klatskin tumors) and distal tumors based on their location [3,4].…”

Section: Introductionmentioning

confidence: 99%

The Plasma LncRNA Acting as Fingerprint in Hilar Cholangiocarcinoma

Shi

Zhang

et al. 2018

Cell Physiol Biochem

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Background & Aims: Current studies have indicated that long non-coding RNAs (lncRNAs) could act as tumor biomarkers for disease diagnosis and prognosis prediction. In this study, we mainly focused on determining the expression of circulating lncRNAs in patients suffering for hilar cholangiocarcinoma (HC), aiming to reveal the potential lncRNA as a fingerprint. Methods: A total 12 lncRNAs were previously proven to be aberrantly expressed in HC tumor tissues. All of the 12 lncRNAs were selected as candidate targets for subsequent circulating lncRNA assay. The candidate lncRNAs were validated by qRT-PCR arranged in training and validation sets. The risk score analysis was employed. Data was presented with receiver operating characteristic curve (ROC). Results: Circulating PCAT1, MALAT1, and CPS1-IT1 were significantly increased in plasma samples of HC patients in both the training set and validation set. Through ROC analysis, we found that the three plasmatic lncRNAs presented the area under ROC curve value (AUC) as 0.784, 0.860, and 0.677. Further combination with the three factors indicated a higher power (AUC, 0.893; sensitivity, 85.5%; specificity, 93.2%). Conclusion: This was the first time to reveal the potential circulating fingerprints for predicting HC. PCAT1, MALAT1, and CPS1-IT1 may act as novel early diagnosis biomarkers for predicting HC.

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“…Given the limited survival advantage of GemCis, it has been suggested that some patients should be enrolled in experimental trials in place of standard‐of‐care . Any experimental trials should require careful biomarker‐driven stratification of prospective responders, given the potential of individual driver mutations to influence diverse pharmacologic responses . Presently, treatment of patients with fibroblast growth factor receptor 2 ( FGFR2 ) fusion–positive intrahepatic CCA (iCCA) with the FGFR2 inhibitor BGJ398 is the only current example of personalized translational success for biliary tumors, significantly extending progression‐free survival .…”

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confidence: 99%

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

et al. 2019

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Cholangiocarcinoma (CCA) mortality rates are increasing as a result of rising incidence and limited curative treatment(s) for patients with advanced disease. NOTCH pathway reactivation has been reported in biliary malignancies to conflicting degrees, hindering prioritization of key therapeutic targets within the network and identification of candidate responder patients for NOTCH‐directed therapies. We analyzed genomic data from 341 patients with CCA and identified NOTCH1 significantly increased in a subgroup characterized by distinct stromal infiltration. Network‐wide imbalance of the NOTCH pathway was seen in CCA, including correlation of NOTCH1 with NOTCH3 and NOTCH ligands. Given the diversity of observed NOTCH receptor engagement, γ‐secretase modulation was rationalized as a therapeutic option. Indeed, subcutaneous transplantation of sensitive and resistant CCA cell lines pretreated with a γ‐secretase inhibitor (GSi) cocktail demonstrated the antineoplastic effects of GSi in a subset of CCA and led to the development of a 225‐gene responder signature. This signature was validated in an independent cohort of 119 patients. Further, this signature was enriched in liver tumors initiated by hydrodynamic injections of activated‐NOTCH as compared with the AKT‐RAS‐driven tumors. Candidate GSi‐responder patients were characterized by distinct transcriptomes overlapping with previous hepatobiliary metastasis and stemness, unique stromal properties, and dysfunctional intratumoral immune infiltration. Pan‐cancer analysis identified 41.9% of cancer types to harbor prospective GSi‐responder patients, which was adapted into a 20‐gene GSi‐sensitivity score metric capable of discriminating nanomolar versus micromolar sensitivity to a cell‐permeable GSi (Z‐LLNle‐CHO) across 60 diverse tumor lines (area under the curve = 1). Conclusion: We have established a GSi‐responder signature with evidence across several patient cohorts, as well as in vitro and in vivo models, to enable precision medicine application of NOTCH‐directed therapy in CCA as well as prospectively across diverse malignancies.

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Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma

Cited by 104 publications

References 47 publications

Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

Exome sequencing of 22 genes using tissue from patients with biliary tract cancer

The Plasma LncRNA Acting as Fingerprint in Hilar Cholangiocarcinoma

Identification of a Pan‐Gamma‐Secretase Inhibitor Response Signature for Notch‐Driven Cholangiocarcinoma

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