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Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.

ABSTRACT: Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% of patients harbored one cancer-associated mutation, with two mutations in 20%. High frequency somatic mutations in genes not typically associated with cholangiocarcinoma included mTOR, ABL1 and NOTCH1. We identified non-synonymous mutation (p.Glu38del) in MAP3K9 in ten tumors, associated with increased peri-vascular invasion (Fisher's exact, p < 0.018). Mutation-enriched pathways were primarily immunological, including innate Dectin-2 (FDR 0.001) and adaptive T-cell receptor pathways including PD-1 (FDR 0.007), CD4 phosphorylation (FDR 0.009) and ZAP70 translocation (FDR 0.009), with overlapping HLA genes. We observed cancer-associated mutations in over half of our patients. Many of these mutations are not typically associated with cholangiocarcinoma yet may increase eligibility for contemporary targeted trials. We also identified a targetable MAP3K9 mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype.

SUBMITTER: Quinn LM

PROVIDER: S-EPMC10126102 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.

Quinn Leonard M LM Haldenby Sam S Antzcak Philip P Fowler Anna A Bullock Katie K Kenny John J Gilbert Timothy T Andrews Timothy T Diaz-Nieto Rafael R Fenwick Stephen S Jones Robert R Costello-Goldring Eithne E Poston Graeme G Greenhalf William W Palmer Daniel D Malik Hassan H Goldring Chris C

Scientific reports 20230424 1

Peri-hilar cholangiocarcinoma (pCCA) is chemorefractory and limited genomic analyses have been undertaken in Western idiopathic disease. We undertook comprehensive genomic analyses of a U.K. idiopathic pCCA cohort to characterize its mutational profile and identify new targets. Whole exome and targeted DNA sequencing was performed on forty-two resected pCCA tumors and normal bile ducts, with Gene Set Enrichment Analysis (GSEA) using one-tailed testing to generate false discovery rates (FDR). 60% ...[more]

PMID: 37095160

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Project description:BackgroundCholangiocarcinoma (CCA) is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver. Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease.AimTo determine the molecular pathogenesis in CCA progression.MethodsIn silico analysis, in vitro cell culture, CCA transgenic animals, histological, and molecular assays were adopted to determine the molecular pathogenesis.ResultsThe transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas (TGCA, CHOL), European Bioinformatics Institute (EBI, GAD00001001076), and Gene Expression Omnibus (GEO, GSE107943) databases. Using Gene set enrichment analysis, the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets. We, through differentially expressed genes, found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples. The associated genes, via quantitative real-time PCR and western blotting assays, were further examined in normal human cholangiocytes, CCA cell lines, mouse normal bile ducts, and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver. Consistently, we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors. Interestingly, targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy. More importantly, we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test.ConclusionIn summary, our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.

Dataset Information

Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.

Publications

Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.

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