Targeted genomic profiling revealed a unique clinical phenotype in intrahepatic cholangiocarcinoma with fibroblast growth factor receptor rearrangement.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhu Z
PROVIDER: S-EPMC8283138 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundThe molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection.MethodsMultiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined.ResultsThe majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis.ConclusionsMost somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.
| S-EPMC4324507 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a treatment-refractory primary liver cancer with an increasing incidence and mortality worldwide in recent years. Lack of a stereotyped genetic signature and limited understanding of genomic landscape make the development of effective targeted therapies challenging. Recent application of advanced technologies such as next-generation sequencing (NGS) has broadened our understanding of genetic heterogeneity in iCCA and many potentially actionable genetic alterations have been identified. This review explores the recent advances in defining genetic alterations in iCCAs, which may present potent therapeutic targets. Chromatin remodeling genes and genes encoding isocitrate dehydrogenase and tyrosine kinase receptors as well as their downstream effectors are among the most frequently altered genes. Clinical trials testing the effect of new targeted agents on iCCA patients, especially those with the above genetic markers are under way. However, the complex interplay of environmental and evolutionary factors contributing to the genetic variability in iCCA calls for a more cautionary use of NGS in tailoring targeted regimen to the patients. Next-generation functional testing may complement NGS to execute precision medicine in future.
| S-EPMC4851838 | biostudies-literature
Project description:We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.
| S-EPMC8317046 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, "undetermined"). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, comutation profiles, and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all three mutations ("undetermined") harbored the most extensive structural alterations, while isocitrate dehydrogenase mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.ConclusionStratification of intrahepatic cholangiocarcinoma patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epimutational) that influence pharmacologic response in drug repositioning protocols; this genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. (Hepatology 2018).
| S-EPMC6599967 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer arising from the bile ducts with a need for earlier diagnosis and a greater range of treatment options. KRAS/NRAS mutations are common in ICC tumours and 6-32% of patients also have isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations associated with metabolic changes. This feasibility study investigated sequencing circulating tumour DNA (ctDNA) combined with metabolite profiling of plasma as a method for biomarker discovery in ICC patients. Plasma was collected from four ICC patients receiving radio-embolisation and healthy controls at multiple time points. ctDNA was sequenced using Ampliseq cancer hotspot panel-v2 on Ion Torrent PGM for single nucleotide variants (SNV) detection and with Illumina whole genome sequencing for copy number variants (CNV) and further targeted examination for SNVs. Untargeted analysis of metabolites from patient and control plasma was performed using liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS). Metabolite identification was performed using multi-parameter comparisons with analysis of authentic standards, and univariate statistical analysis was performed to identify differences in metabolite abundance between patient and control samples. Recurrent somatic SNVs and CNVs were identified in ctDNA from three out of four patients that included both NRAS and IDH1 mutations linked to ICC. Plasma metabolite analysis revealed biomarker metabolites associated with ICC and in particular 2-hydroxyglutarate (2-HG) levels were elevated in both samples from the only patient showing a variant allele in IDH1. A reduction in the number of CNVs was observed with treatment. This study demonstrates that ctDNA and metabolite levels can be identified and correlated in ICC patient blood samples and differentiated from healthy controls. We conclude that combining genomic and metabolic analysis of plasma offers an effective approach to biomarker identification with potential for disease stratification and early detection studies.
| S-EPMC6966597 | biostudies-literature
Project description:BackgroundTreatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies.MethodsThis multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided.ResultsAmong 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P < .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P < .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P < .001).ConclusionsPatients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.
| S-EPMC10323903 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819).
| S-EPMC4778675 | biostudies-literature
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive primary liver tumor, characterized by a range of different clinical manifestations and by increasing incidence and mortality rates even after curative treatment with radical resection. In recent years, growing attention has been devoted to this disease and some evidence supports liver transplantation (LT) as an appropriate treatment for intrahepatic cholangiocarcinoma; evolving work has also provided a framework for better understanding the genetic basis of this cancer. The aim of this study was to provide a clinical description of our series of patients complemented with Next-Generation Sequencing genomic profiling. From 1999 to 2021, 12 patients who underwent LT with either iCCA or a combined hepatocellular and cholangiocellular carcinoma (HCC-iCCA) were included in this study. Mutations were observed in gene activating signaling pathways known to be involved with iCCA tumorigenesis (KRAS/MAPK, P53, PI3K-Akt/mTOR, cAMP, WNT, epigenetic regulation and chromatin remodeling). Among several others, a strong association was observed between the Notch pathway and tumor size (point-biserial rhopb = 0.93). Our results are suggestive of the benefit potentially derived from molecular analysis to improve our diagnostic capabilities and to devise new treatment protocols, and eventually ameliorate long-term survival of patients affected by iCCA or HCC-iCCA.
| S-EPMC8657183 | biostudies-literature
Project description:BackgroundIntrahepatic Cholangiocarcinoma (iCCA) is characterized by a strong stromal reaction playing a role in tumor progression. Thymus cell antigen 1 (THY1), also called Cluster of Differentiation 90 (CD90), is a key regulator of cell-cell and cell-matrix interaction. In iCCA, CD90 has been reported to be associated with a poor prognosis. In an iCCA PDX model, we recently found that CD90 was downregulated in mice treated with the Notch γ-secretase inhibitor Crenigacestat. The study aims to investigate the role of CD90 in relation to the NOTCH pathway.MethodsTHY1/CD90 gene and protein expression was evaluated in human iCCA tissues and xenograft models by qRT-PCR, immunohistochemistry, and immunofluorescence. Notch1 inhibition was achieved by siRNA. THY1/CD90 functions were investigated in xenograft models built with HuCCT1 and KKU-M213 cell lines, engineered to overexpress or knockdown THY1, respectively.ResultsCD90 co-localized with EPCAM, showing its epithelial origin. In vitro, NOTCH1 silencing triggered HES1 and THY1 down-regulation. RBPJ, a critical transcriptional regulator of NOTCH signaling, exhibited putative binding sites on the THY1 promoter and bound to the latter, implying CD90 as a downstream NOTCH pathway effector. In vivo, Crenigacestat suppressed iCCA growth and reduced CD90 expression in the PDX model. In the xenograft model, Crenigacestat inhibited tumor growth of HuCCT1 cells transfected to overexpress CD90 and KKU-M213 cells constitutively expressing high levels of CD90, while not affecting the growth of HuCCT1 control cells and KKU-M213 depleted of CD90. In an iCCA cohort, patients with higher expression levels of NOTCH1/HES1/THY1 displayed a significantly shorter survival.ConclusionsiCCA patients with higher NOTCH1/HES1/THY1 expression have the worst prognosis, but they are more likely to benefit from Notch signaling inhibition. These findings represent the scientific rationale for testing NOTCH1 inhibitors in clinical trials, taking the first step toward precision medicine for iCCA.
| S-EPMC8851853 | biostudies-literature
Project description:IntroductionData on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited.MethodsPatients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases.ResultsAmong 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients.ConclusionsEarly-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.
| S-EPMC10997729 | biostudies-literature