Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA547577 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genome-wide expression analysis of 182 extrahepatic cholangiocarcinoma and 38 non-tumoral bile duct samples as part of a integrated study of gene expression and targeted DNA-sequencing in patients with extrahepatic cholangiocarcinoma We used whole-genome transcriptome to conduct an unsupervised molecular classification of extrahepatic cholangiocarcinoma
2020-03-22 | GSE132305 | GEO
Project description:Background & aimsCholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies.MethodsAn integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC.ResultsKRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFβ signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors.ConclusionAn integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches.Lay summaryTargeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.
| S-EPMC8418904 | biostudies-literature
Project description:The role HOXA5 in extrahepatic cholangiocarcinoma
| PRJNA872542 | ENA
Project description:Homeobox A5 (HOXA5) is a transcription factor in mammalian and can regulate cell differentiation, proliferation and apoptosis as well as tumorigenesis. However, little is known on whether and how HOXA5 can regulate the malignant behaviors of cholangiocarcinoma. The methylation levels of HOXA5 were evaluated by methylation microarray and bisulfite sequencing PCR. We found that hypermethylation in the HOXA5 promoter down-regulated HOXA5 expression in extrahepatic cholangiocarcinoma (ECCA) tissues, which was correlated with worse overall survival. HOXA5 over-expression significantly inhibited the proliferation and tumor growth.
2022-10-05 | GSE211911 | GEO
Project description:The overall objective of this study was to explore aberrantly expressed microRNAs (miRNAs) and investigate their clinical significances in patients with extrahepatic cholangiocarcinoma (ECCA).
2019-09-18 | GSE137590 | GEO
Project description:The role HOXA5 in extrahepatic cholangiocarcinoma (Expression)
| PRJNA872543 | ENA
Project description:The role HOXA5 in extrahepatic cholangiocarcinoma (Methylation)
| PRJNA872545 | ENA
Project description:Transcriptomic profiling Background Cholangiocarcinoma accounts for 5-10% of primary hepatic cancers. The etiology is unclear and patients are often diagnosed without risk factors. Resection is the only curative treatment although patients frequently remain undiagnosed until advanced stage of disease. Methods To construct molecular classification of cholangiocarcinoma, we profiled the transcriptomes of 104 freshly-frozen tumors and 59 matched non-cancerous livers obtained from Australia, Europe and the United States. We also performed mutational analysis of KRAS, EGFR and BRAF, and used laser-capture microdissection to obtain independent gene expression profiles for epithelial and stromal compartments in a subset of tumors. The selected target genes were validated by western blotting and immunohistochemistry. Results Transcriptomic profiling classified cholangiocarcinoma into two distinct subclasses defined by survival (P<0.0007) and early recurrence (P<0.001). Applying leave-one-out cross-validation, we optimized the prognostic classifier to 238 genes which were positively enriched in the epithelial tumor compartment. A deregulated HER2 network was associated with the epithelial compartment which also showed a frequent overexpression of Ki67, EGFR, MET and pRPS6 whereas inflammatory cytokines were enriched in tumor stroma specifically in patients with poor prognosis. KRAS mutations were found in 24.6% of patients with poor disease outcome. Conclusion Our study presents new insights into pathogenesis of cholangiocarcinoma and stratification of the patients according to survival and recurrence. Identification of a subgroup of patients among the poor prognostic cohort characterized by KRAS mutations and oncogenic-addiction may provide a novel therapeutic opportunity for this treatment-refractory malignancy. Profiling of individual cholangiocarcinomas and non-cancerous matched surrounding livers using normal bile ducts as reference
2012-02-25 | E-GEOD-26566 | biostudies-arrayexpress
Project description:Transcriptomic profiling Background Cholangiocarcinoma accounts for 5-10% of primary hepatic cancers. The etiology is unclear and patients are often diagnosed without risk factors. Resection is the only curative treatment although patients frequently remain undiagnosed until advanced stage of disease. Methods To construct molecular classification of cholangiocarcinoma, we profiled the transcriptomes of 104 freshly-frozen tumors and 59 matched non-cancerous livers obtained from Australia, Europe and the United States. We also performed mutational analysis of KRAS, EGFR and BRAF, and used laser-capture microdissection to obtain independent gene expression profiles for epithelial and stromal compartments in a subset of tumors. The selected target genes were validated by western blotting and immunohistochemistry. Results Transcriptomic profiling classified cholangiocarcinoma into two distinct subclasses defined by survival (P<0.0007) and early recurrence (P<0.001). Applying leave-one-out cross-validation, we optimized the prognostic classifier to 238 genes which were positively enriched in the epithelial tumor compartment. A deregulated HER2 network was associated with the epithelial compartment which also showed a frequent overexpression of Ki67, EGFR, MET and pRPS6 whereas inflammatory cytokines were enriched in tumor stroma specifically in patients with poor prognosis. KRAS mutations were found in 24.6% of patients with poor disease outcome. Conclusion Our study presents new insights into pathogenesis of cholangiocarcinoma and stratification of the patients according to survival and recurrence. Identification of a subgroup of patients among the poor prognostic cohort characterized by KRAS mutations and oncogenic-addiction may provide a novel therapeutic opportunity for this treatment-refractory malignancy.
2012-02-25 | GSE26566 | GEO
Project description:Biliary tract cancer (BTC) ranks among the most lethal human malignancies, thereby representing an unmet clinical need. In this study, we find that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible towards transformation by activated Pik3caH1047R, but completely refractory to oncogenic KrasG12D. Using genome-wide in vivo piggyBac transposon-based forward genetic screening and genetic loss-of-function experiments, we discover important extrahepatic cholangiocarcinoma (ECC) cancer genes and find that PI3K-signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts the pancreas, where oncogenic Kras in concert with Trp53 loss of function are key cancer drivers. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development, and bypasses oncogene-induced senescence without triggering the Trp53 pathway. These studies provide a mechanistic link between PI3K-signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor-subtype.
2021-07-05 | E-MTAB-10515 | biostudies-arrayexpress