Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.

Autor: Plum PS; Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany., Hess T; Center for Human Genetics, University Hospital of Marburg, Marburg, Germany., Bertrand D; Computational and Systems Biology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Morgenstern I; General, Visceral and Transplant Surgery, Johannes Gutenberg University, Mainz, Germany., Velazquez Camacho O; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Jonas C; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Alidousty C; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Wagner B; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Roessler S; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany., Albrecht T; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany., Becker J; Institute of Human Genetics, University Hospital of Bonn, Bonn, Germany., Richartz V; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Holz B; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Hoppe S; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Poh HM; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Chia BKH; Computational and Systems Biology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Chan CX; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Pathiraja T; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Teo AS; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Marquardt JU; I Department of Medicine, Johannes Gutenberg University, Mainz, Germany.; Department of Medicine, University Hospital Schleswig-Holstein, Lübeck, Germany., Khng A; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Heise M; General, Visceral and Transplant Surgery, Johannes Gutenberg University, Mainz, Germany.; Department for General, Visceral and Transplant Surgery, University Hospital Frankfurt, Goethe-University Frankfurt/Main, Frankfurt, Germany., Fei Y; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Thieme R; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany., Klein S; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Hong JH; Duke-NUS Medical School, Cancer and Stem Cell Biology, Singapore, Singapore.; Division of Medical Science, Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore, Singapore., Dima SO; Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania., Popescu I; Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania., Hoppe-Lotichius M; General, Visceral and Transplant Surgery, Johannes Gutenberg University, Mainz, Germany., Buettner R; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Lautem A; General, Visceral and Transplant Surgery, Johannes Gutenberg University, Mainz, Germany., Otto G; Emeritus of the Division of Transplantation Surgery, University Medical Center, Mainz, Germany., Quaas A; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Nagarajan N; Computational and Systems Biology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Rozen S; Duke-NUS Medical School, Cancer and Stem Cell Biology, Singapore, Singapore., Teh BT; Duke-NUS Medical School, Cancer and Stem Cell Biology, Singapore, Singapore., Goeppert B; RKH Klinikum Ludwigsburg, Institute of Pathology and Neuropathology, Ludwigsburg, Germany.; Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland., Drebber U; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Lang H; General, Visceral and Transplant Surgery, Johannes Gutenberg University, Mainz, Germany., Tan P; Duke-NUS Medical School, Cancer and Stem Cell Biology, Singapore, Singapore.; Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore., Gockel I; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany., Schumacher J; Center for Human Genetics, University Hospital of Marburg, Marburg, Germany., Hillmer AM; Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.; Cancer Therapeutics and Stratified Oncology, Agency for Science, Technology and Research (A*STAR), Genome Institute of Singapore, Singapore, Singapore.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2024 Jun; Vol. 14 (6), pp. e1723.
DOI: 10.1002/ctm2.1723
Abstrakt: Background: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease.
Methods: We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany.
Results: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs.
Conclusions: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.
(© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
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