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Volume 12
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Article

Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities

by
Alexander Scheiter
1,2,*,
Frederik Hierl
1,
Ingrid Winkel
1,
Felix Keil
1,
Margit Klier-Richter
1,
Cédric Coulouarn
3,
Florian Lüke
2,4,5,
Arne Kandulski
6,
Matthias Evert
1,
Wolfgang Dietmaier
1,
Diego F. Calvisi
1 and
Kirsten Utpatel
1
1
Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany
2
Bavarian Center for Cancer Research/BZKF, 91054 Bavaria, Germany
3
INSERM, Université de Rennes, F-35042 Rennes, France
4
Department of Internal Medicine III, University Hospital Regensburg, Hematology and Oncology, 93053 Regensburg, Germany
5
Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, 93053 Regensburg, Germany
6
Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2022, 12(8), 1270; https://doi.org/10.3390/jpm12081270
Submission received: 17 June 2022 / Revised: 20 July 2022 / Accepted: 29 July 2022 / Published: 1 August 2022
(This article belongs to the Special Issue Precision Medicine in Hepatobiliary Cancer: Preclinical and Clinical Evidence)
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Abstract

Cholangiocarcinoma (CCA) features a dismal prognosis with limited treatment options. Genomic studies have unveiled several promising targets in this disease, including fibroblast growth factor receptor (FGFR) fusions and isocitrate dehydrogenase (IDH) mutations. To fully harness the potential of genomically informed therapies in CCA, it is necessary to thoroughly characterize the available model organisms, including cell lines. One parameter to investigate in CCA is homologous recombination deficiency (HRD). While mutations in homologous recombinational repair (HRR)-related genes have been detected, their predictive value remains undetermined. Using a targeted next-generation sequencing approach, we analyzed 12 human CCA cell lines and compared them to 62 CCA samples of the molecular tumor board cohort. The AmoyDx® HRD Focus Panel was employed to determine corresponding genomic scar scores (GSS). Ten of twelve cell lines harbored alterations in common HRR-related genes, and five cell lines were HRD-positive, although this parameter did not correlate well with Olaparib sensitivity. Moreover, functionally relevant APC and β-catenin mutations were registered, which were also detected in 4/176 (2.3%) samples on a CCA microarray. Although rare, these alterations were exclusive to large duct type CCA with associated intraductal papillary neoplasms of the bile duct (IPNB) in 3 cases, pointing at a distinct form of cholangiocarcinogenesis with potential specific vulnerabilities.
Keywords: cholangiocarcinoma; β-catenin; WNT; APC; HRD; Olaparib; PARP; intraductal papillary neoplasm of the bile duct cholangiocarcinoma; β-catenin; WNT; APC; HRD; Olaparib; PARP; intraductal papillary neoplasm of the bile duct

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MDPI and ACS Style

Scheiter, A.; Hierl, F.; Winkel, I.; Keil, F.; Klier-Richter, M.; Coulouarn, C.; Lüke, F.; Kandulski, A.; Evert, M.; Dietmaier, W.; et al. Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities. J. Pers. Med. 2022, 12, 1270. https://doi.org/10.3390/jpm12081270

AMA Style

Scheiter A, Hierl F, Winkel I, Keil F, Klier-Richter M, Coulouarn C, Lüke F, Kandulski A, Evert M, Dietmaier W, et al. Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities. Journal of Personalized Medicine. 2022; 12(8):1270. https://doi.org/10.3390/jpm12081270

Chicago/Turabian Style

Scheiter, Alexander, Frederik Hierl, Ingrid Winkel, Felix Keil, Margit Klier-Richter, Cédric Coulouarn, Florian Lüke, Arne Kandulski, Matthias Evert, Wolfgang Dietmaier, and et al. 2022. "Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities" Journal of Personalized Medicine 12, no. 8: 1270. https://doi.org/10.3390/jpm12081270

APA Style

Scheiter, A., Hierl, F., Winkel, I., Keil, F., Klier-Richter, M., Coulouarn, C., Lüke, F., Kandulski, A., Evert, M., Dietmaier, W., Calvisi, D. F., & Utpatel, K. (2022). Wnt/β-Catenin-Pathway Alterations and Homologous Recombination Deficiency in Cholangiocarcinoma Cell Lines and Clinical Samples: Towards Specific Vulnerabilities. Journal of Personalized Medicine, 12(8), 1270. https://doi.org/10.3390/jpm12081270

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