Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis

• Verfasst von: Grimsrud, Marit M. [VerfasserIn]
• Verfasst von: Forster, Michael [VerfasserIn]
• Verfasst von: Goeppert, Benjamin [VerfasserIn]
• Verfasst von: Hemmrich-Stanisak, Georg [VerfasserIn]
• Verfasst von: Sax, Irmi [VerfasserIn]
• Verfasst von: Grzyb, Krzysztof [VerfasserIn]
• Verfasst von: Braadland, Peder R. [VerfasserIn]
• Verfasst von: Charbel, Alphonse [VerfasserIn]
• Verfasst von: Metzger, Carmen [VerfasserIn]
• Verfasst von: Albrecht, Thomas [VerfasserIn]
• Verfasst von: Steiert, Tim Alexander [VerfasserIn]
• Verfasst von: Schlesner, Matthias [VerfasserIn]
• Verfasst von: Manns, Michael P. [VerfasserIn]
• Verfasst von: Vogel, Arndt [VerfasserIn]
• Verfasst von: Yaqub, Sheraz [VerfasserIn]
• Verfasst von: Karlsen, Tom H. [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Verfasst von: Boberg, Kirsten M. [VerfasserIn]
• Verfasst von: Franke, Andre [VerfasserIn]
• Verfasst von: Rössler, Stephanie [VerfasserIn]
• Verfasst von: Folseraas, Trine [VerfasserIn]
• Titel: Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis
• Verf.angabe: Marit M. Grimsrud, Michael Forster, Benjamin Goeppert, Georg Hemmrich-Stanisak, Irmi Sax, Krzysztof Grzyb, Peder R. Braadland, Alphonse Charbel, Carmen Metzger, Thomas Albrecht, Tim Alexander Steiert, Matthias Schlesner, Michael P. Manns, Arndt Vogel, Sheraz Yaqub, Tom H. Karlsen, Peter Schirmacher, Kirsten M. Boberg, Andre Franke, Stephanie Roessler, Trine Folseraas
• E-Jahr: 2024
• Jahr: July 2024
• Umfang: 17 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 14.01.2025
• Titel Quelle: Enthalten in: Hepatology communications
• Ort Quelle: [Alphen aan den Rijn] : Wolters Kluwer Health, 2017
• Jahr Quelle: 2024
• Band/Heft Quelle: 8(2024), 7 vom: Juli, Artikel-ID e0461, Seite 1-17
• ISSN Quelle: 2471-254X
• DOI: doi:10.1097/HC9.0000000000000461
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1914549821

Abstract

Background: - People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. - Methods: - We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. - Results: - We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. - Conclusions: - In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.