Quinn, Leonard M, Haldenby, Sam, Antzcak, Philip, Fowler, Anna, Bullock, Katie 
ORCID: 0000-0002-5758-0179, Kenny, John, Gilbert, Timothy, Andrews, Timothy, Diaz-Nieto, Rafael, Fenwick, Stephen et al (show 7 more authors)
(2023)
Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.
Scientific Reports, 13 (1).
6681-.
Abstract
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>mTOR, ABL1</jats:italic> and <jats:italic>NOTCH1</jats:italic>. We identified non-synonymous mutation (p.Glu38del) in <jats:italic>MAP3K9</jats:italic> 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 <jats:italic>MAP3K9</jats:italic> mutation, in addition to oncogenic and immunological pathways hitherto not described in any cholangiocarcinoma subtype.</jats:p>
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Bile Ducts, Intrahepatic, Humans, Cholangiocarcinoma, Bile Duct Neoplasms, MAP Kinase Kinase Kinases, DNA Mutational Analysis, Genomics, Mutation, Klatskin Tumor |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Population Health |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 26 Apr 2023 10:29 |
| Last Modified: | 09 Aug 2023 09:08 |
| DOI: | 10.1038/s41598-023-33096-0 |
| Open Access URL: | https://doi.org/10.1038/s41598-023-33096-0 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3169983 |
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