1. Genomic profiling of idiopathic peri-hilar cholangiocarcinoma reveals new targets and mutational pathways.
- Author
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Quinn, Leonard M., Haldenby, Sam, Antzcak, Philip, Fowler, Anna, Bullock, Katie, Kenny, John, Gilbert, Timothy, Andrews, Timothy, Diaz-Nieto, Rafael, Fenwick, Stephen, Jones, Robert, Costello-Goldring, Eithne, Poston, Graeme, Greenhalf, William, Palmer, Daniel, Malik, Hassan, and Goldring, Chris
- Subjects
CHOLANGIOCARCINOMA ,FALSE discovery rate ,GENOMICS ,BILE ducts ,DNA sequencing ,IDIOPATHIC diseases - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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