Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors

Lino Möhrmann¹, Lysann Rostock², Maximilian Werner³, Małgorzata Oleś⁴, Jonas S Arnold⁵, Nagarajan Paramasivam⁴, Korinna Jöhrens⁶, Luise Rupp⁷, Marc Schmitz⁷, Daniela Richter², Sebastian Uhrig⁴, Martina Fröhlich⁴, Barbara Hutter⁴, Jennifer Hüllein⁴, Arne Jahn⁵, Marie Arlt⁵, Elena E Möhrmann³, Dorothea Hanf³, Laura Gieldon⁸, Simon Kreutzfeldt⁹, Christoph E Heilig⁹, Maria-Veronica Teleanu⁹, Daniel B Lipka¹⁰, Katja Beck⁸, Annika Baude-Müller¹¹, Andreas Mock¹², Ivan Jelas¹³, Damian T Rieke¹³, Marcel Wiesweg¹⁴, Christian Brandts¹⁵, Melanie Boerries¹⁶, Anna L Illert¹⁷, Alexander Desuki¹⁸, Thomas Kindler¹⁸, Angela M Krackhardt¹⁹, C Benedikt Westphalen²⁰, Petros Christopoulos²¹, Leonidas Apostolidis²², Albrecht Stenzinger²³, Michael Allgäuer²³, Olaf Neumann²³, Irina A Kerle³, Peter Horak⁹, Christoph Heining³, Heidrun Grosch²¹, Evelin Schröck⁵, Daniel Hübschmann²⁴, Stefan Fröhling²⁵, Hanno Glimm²⁶

Affiliations

¹ Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, USA; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. Electronic address: lino.moehrmann@nct-dresden.de.
² Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.
³ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany.
⁴ Computational Oncology Group (CO), Molecular Precision Oncology Program (MPOP), German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
⁵ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Institute for Clinical Genetics, University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
⁶ Department of Pathology, University Hospital Carl Gustav Carus, Dresden, Germany.
⁷ Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany.
⁸ Institute of Medical Genetics, Carl von Ossietzky University, Oldenburg, Germany.
⁹ Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, Heidelberg, Germany.
¹⁰ Section Translational Cancer Epigenomics, Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹¹ Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, Heidelberg, Germany; Section Translational Cancer Epigenomics, Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹² Institute of Pathology, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.
¹³ Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁴ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
¹⁵ Department of Medicine, Hematology/Oncology, University Hospital, Goethe University, Frankfurt, Germany; University Cancer Center Frankfurt (UCT), University Hospital, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁶ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
¹⁷ Department of Internal Medicine I, Division of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg im Breisgau, Germany; Klinik und Poliklinik für Innere Medizin III, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
¹⁸ University Cancer Center and Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany; TRON-Translational Oncology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; DKTK, partner site Frankfurt/Mainz, a partnership between DKFZ and University Medical Center Mainz, Mainz, Germany.
¹⁹ Klinik und Poliklinik für Innere Medizin III, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
²⁰ Department of Internal Medicine III, University Hospital, LMU Munich and Comprehensive Cancer Center, Munich, Germany.
²¹ Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital, and NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center, member of the German Center for Lung Research (DZL), Heidelberg, Germany.
²² Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
²³ Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
²⁴ Computational Oncology Group (CO), Molecular Precision Oncology Program (MPOP), German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany; Innovation and Service Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
²⁵ Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
²⁶ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Translational Functional Cancer Genomics, DKFZ Heidelberg, Heidelberg, Germany. Electronic address: hanno.glimm@nct-dresden.de.

PMID: 40107270
DOI: 10.1016/j.medj.2025.100612

Free article

Observational Study

Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors

Lino Möhrmann et al. Med. 2025.

Free article

. 2025 Jun 13;6(6):100612.

doi: 10.1016/j.medj.2025.100612. Epub 2025 Mar 18.

Authors

Affiliations

¹ Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, USA; Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. Electronic address: lino.moehrmann@nct-dresden.de.
² Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany.
³ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany.
⁴ Computational Oncology Group (CO), Molecular Precision Oncology Program (MPOP), German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
⁵ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Institute for Clinical Genetics, University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; ERN GENTURIS, Hereditary Cancer Syndrome Center Dresden, Dresden, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
⁶ Department of Pathology, University Hospital Carl Gustav Carus, Dresden, Germany.
⁷ Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany.
⁸ Institute of Medical Genetics, Carl von Ossietzky University, Oldenburg, Germany.
⁹ Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, Heidelberg, Germany.
¹⁰ Section Translational Cancer Epigenomics, Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹¹ Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, Heidelberg, Germany; Section Translational Cancer Epigenomics, Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹² Institute of Pathology, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.
¹³ Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁴ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
¹⁵ Department of Medicine, Hematology/Oncology, University Hospital, Goethe University, Frankfurt, Germany; University Cancer Center Frankfurt (UCT), University Hospital, Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁶ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, and Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
¹⁷ Department of Internal Medicine I, Division of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg im Breisgau, Germany; Klinik und Poliklinik für Innere Medizin III, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
¹⁸ University Cancer Center and Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany; TRON-Translational Oncology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany; DKTK, partner site Frankfurt/Mainz, a partnership between DKFZ and University Medical Center Mainz, Mainz, Germany.
¹⁹ Klinik und Poliklinik für Innere Medizin III, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
²⁰ Department of Internal Medicine III, University Hospital, LMU Munich and Comprehensive Cancer Center, Munich, Germany.
²¹ Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital, and NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany; Translational Lung Research Center, member of the German Center for Lung Research (DZL), Heidelberg, Germany.
²² Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
²³ Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
²⁴ Computational Oncology Group (CO), Molecular Precision Oncology Program (MPOP), German Cancer Research Center (DKFZ), Heidelberg, Germany; National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany; Innovation and Service Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.
²⁵ Division of Translational Medical Oncology, DKFZ, Heidelberg, Germany; NCT Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
²⁶ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT Dresden, a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Germany; Translational Medical Oncology, Faculty of Medicine, and University Hospital Carl Gustav Carus, TU Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; Translational Functional Cancer Genomics, DKFZ Heidelberg, Heidelberg, Germany. Electronic address: hanno.glimm@nct-dresden.de.

PMID: 40107270
DOI: 10.1016/j.medj.2025.100612

Abstract

Background: Thymic epithelial tumors (TETs) are rare malignancies with limited treatment options and underexplored molecular features.

Methods: We examined the genomic landscape and therapeutic outcomes in 81 patients with advanced TETs, including thymic carcinomas (TCs), thymomas, and thymic neuroendocrine neoplasms (TNENs), who were enrolled in the MASTER trial, a prospective observational precision oncology trial.

Findings: Using whole-genome-sequencing and whole-exome-sequencing analysis, transcriptome analysis, and methylome analysis, we identified distinct molecular features across TET subtypes, including a higher tumor mutational burden in TC and pathogenic germline variants in 18% of cases. We performed transcriptome- and methylome-based unsupervised clustering and were able to divide TCs into immunologically hot and cold subsets, with hot TCs exhibiting higher T cell infiltration and significantly longer overall survival. In 65 out of 76 (86%) patients, we recommended molecularly informed therapies, which were applied in 29 out of 65 (45%) cases, leading to a disease control rate of 62% and an objective response rate of 23% (both n = 26). The progression-free survival ratio (PFSr) was > 1.3 in 8 out of 24 (33%) patients, 7 of them having TC. Among TCs, patients achieved a mean PFSr of 1.4, indicating potential therapeutic advantages in this subgroup. The PFSr between the PFS of immune checkpoint inhibition and preceding therapies was significantly higher in the hot cluster compared to the cold cluster (median 1.7 vs. 0.3; p = 0.01945).

Conclusions: Our findings expand the understanding of TET biology and emphasize the role of precision oncology in informing treatment decisions and improving outcomes for patients with advanced TETs, particularly in TCs.

Keywords: Translation to patients; molecular profiling; multiomics; precision oncology; prospective observational study; targeted therapy; thymic carcinoma; thymic epithelial tumor; thymic neuroendocrine neoplasm; thymoma; whole-genome sequencing.

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Conflict of interest statement

Declaration of interests A.S. is on the advisory board/speakers’ bureau for Aignostics, Amgen, Astellas, AstraZeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Seagen, Servier, Takeda, and Thermo Fisher. He has received grants from Bayer, BMS, Chugai, and Incyte. C.H. has received honoraria from Roche and Novartis and research funding from Boehringer Ingelheim and consults for or is on the advisory board of Boehringer Ingelheim. D.B.L. works as a drug safety physician for Infectopharm. D.T.R. has received honoraria from Bayer, BMS, Eli Lilly, and Roche. M.A. has received honoraria from Boehringer Ingelheim. E.E.M. became an employee of Pfizer Pharma GmbH after participating in this research project. The wife of L.M. is an employee of Pfizer Pharma GmbH. P.C. has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Novartis, Roche, and Takeda; speaker’s honoraria from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, and Takeda; support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Janssen, Gilead, Novartis, Pfizer, and Takeda; and personal fees for participating in advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda, and Roche, all of which are outside the submitted work. S.F. reports consultancy fees from Bayer, Illumina, and Roche; honoraria from Amgen, Eli Lilly, PharmaMar, and Roche; research funding from AstraZeneca, Pfizer, PharmaMar, and Roche; and travel or accommodation expenses from Amgen, Eli Lilly, Illumina, PharmaMar, and Roche.

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Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors

Affiliations

Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources

Full Text Sources

Medical