Skip to main content

Genetic Characterization of Primary Mediastinal B-Cell Lymphoma: Pathogenesis and Patient Outcomes

Authors: Daniel Noerenberg, MD https://orcid.org/0000-0001-5192-6493, Franziska Briest, PhD https://orcid.org/0000-0001-5969-9467, Cornelius Hennch, MD https://orcid.org/0000-0003-4104-5531, Kenichi Yoshida, PhD https://orcid.org/0000-0003-4612-2778, Raphael Hablesreiter, MSc https://orcid.org/0000-0002-4586-932X, Yasuhide Takeuchi, MD https://orcid.org/0000-0002-1262-2355, Hiroo Ueno, MD, Annette M. Staiger, PhD https://orcid.org/0000-0002-5896-3200, Marita Ziepert, PhD, Fazila Asmar, MD, Benjamin N. Locher, MSc https://orcid.org/0000-0002-8482-4984, Erika Toth, MD, PhD https://orcid.org/0000-0003-2054-8447, Thomas Weber, MD, Rose-Marie Amini, MD, PhD https://orcid.org/0000-0003-0901-5252, Wolfram Klapper, MD, Maria Bouzani, MD, Viola Poeschel, MD, Andreas Rosenwald, MD, Gerhard Held, MD, Elías Campo, MD, PhD https://orcid.org/0000-0001-9850-9793, Naveed Ishaque, PhD, Kostas Stamatopoulos, MD, PhD, George Kanellis, MD, Ioannis Anagnostopoulos, MD, Lars Bullinger, MD https://orcid.org/0000-0002-5890-5510, Neta Goldschmidt, MD, Pier Luigi Zinzani, MD, PhD https://orcid.org/0000-0002-2112-2651, Csaba Bödör, PhD https://orcid.org/0000-0002-0729-692X, Richard Rosenquist, MD, PhD https://orcid.org/0000-0002-0211-8788, Theodoros P. Vassilakopoulos, MD, PhD https://orcid.org/0000-0001-8766-1853, German Ott, MD https://orcid.org/0000-0001-7990-6793, Seishi Ogawa, MD, PhD https://orcid.org/0000-0002-7778-5374, and Frederik Damm, MD https://orcid.org/0000-0001-5553-1173 [email protected]Authors Info & Affiliations
Publication: Journal of Clinical Oncology

Abstract

Purpose

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive lymphoma predominantly affecting young female patients. Large-scale genomic investigations and genetic markers for risk stratification are lacking.

Patients and Methods

To elucidate the full spectrum of genomic alterations, samples from 340 patients with previously untreated PMBCL were investigated by whole-genome (n = 20), whole-exome (n = 78), and targeted (n = 308) sequencing. Statistically significant prognostic variables were identified using a multivariable Cox regression model and confirmed by L1/L2 regularized regressions.

Results

Whole-genome sequencing revealed a commonly disrupted p53 pathway with nonredundant somatic structural variations (SVs) in TP53-related genes (TP63, TP73, and WWOX) and identified novel SVs facilitating immune evasion (DOCK8 and CD83). Integration of mutation and copy-number data expanded the repertoire of known PMBCL alterations (eg, ARID1A, P2RY8, and PLXNC1) with a previously unrecognized role for epigenetic/chromatin modifiers. Multivariable analysis identified six genetic lesions with significant prognostic impact. CD58 mutations (31%) showed the strongest association with worse PFS (hazard ratio [HR], 2.52 [95% CI, 1.50 to 4.21]; P < .001) and overall survival (HR, 2.33 [95% CI, 1.14 to 4.76]; P = .02). IPI high-risk patients with mutated CD58 demonstrated a particularly poor prognosis, with 5-year PFS and OS rates of 41% and 58%, respectively. The adverse prognostic significance of the CD58 mutation status was predominantly observed in patients treated with nonintensified regimens, indicating that dose intensification may, to some extent, mitigate the impact of this high-risk marker. By contrast, DUSP2-mutated patients (24%) displayed durable responses (PFS: HR, 0.2 [95% CI, 0.07 to 0.55]; P = .002) and prolonged OS (HR, 0.11 [95% CI, 0.01 to 0.78]; P = .028). Upon CHOP-like treatment, these patients had very favorable outcome, with 5-year PFS and OS rates of 93% and 98%, respectively.

Conclusion

This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

Get full access to this article

View all available purchase options and get full access to this article.

Data Supplements

Authors retain all rights in any data supplements associated with their articles.

The ideas and opinions expressed in this Data Supplement do not necessarily reflect those of the American Society of Clinical Oncology (ASCO). The mention of any product, service, or therapy in this Data Supplement should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify approved uses, the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in this publication or to any errors or omissions. Readers should contact the corresponding author with any comments related to Data Supplement materials.

Prior Presentation

Presented in part at the 2022 Annual Meeting of the European Hematology Association, Vienna, Austria, June 9-12, 2022 (abstract 2, Presidential Symposium); the 2022 Annual Meeting of the American Society of Hematology, New Orleans, LA, GA, December 10-13, 2022, scientific workshop on translational molecular diagnostics.

Support

Supported by grants from the Brigitte und Dr Konstanze Wegener-Stiftung (55), the Else Kröner-Fresenius-Stiftung (2015_A09), Deutsche Krebshilfe (70113148, 70113643), Deutsche José Carreras Leukämie-Stiftung (03 R/2020), and the DKTK, all awarded to F.D. D.N. received support by the BIH clinician scientist program, Lady Tata Memorial Trust, and Deutsche Forschungsgesellschaft (NO1454/1-1). C.H. was supported within the Berlin School of Integrative Oncology's graduate program. B.N.L. was supported by a fellowship from Deutsche José Carreras Leukämie-Stiftung. C.B. was funded by EU's Horizon 2020 Research and Innovation Program under grant agreement No. 739593 and by the Ministry of Innovation and Technology of Hungary from the National Research, Development, and Innovation Fund, financed under the K21_137948, TKP2021-EGA-24, and TKP2021-NVA-15 funding schemes. This work was partially supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Karolinska University Hospital, and Radiumhemmets Forskningsfonder, Stockholm, all awarded to R.R. This work was partially sponsored by MEXT/JSPS KAKENHI (JP26221308, JP26253060), Scientific Research on Innovative Areas (15H05909, 15H05912), JSPS Core-to-Core Program, MEXT as “Priority Issue on Post-K computer,” Grants-in-Aid from the Japan Agency for Medical Research and Development, and AMED (JP15cm0106056, JP19cm0106501, JP16ck0106073, and JP19ck0106250), all awarded to S.O.

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 452 - 466
PubMed: 38055913

History

Published online: December 06, 2023
Published in print: February 01, 2024

Permissions

Request permissions for this article.

Data Sharing Statement

WES bam files have been deposited to the Sequence Read Archive (SRA) and are accessible via BioProject PRJNA851197. Sequencing bam files from whole-genome data are available in the EGA database under the accession code EGAS00001006452.

Authors

Affiliations

Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan
Raphael Hablesreiter, MSc https://orcid.org/0000-0002-4586-932X
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Hiroo Ueno, MD
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology Stuttgart, and University of Tuebingen, Stuttgart, Germany
Marita Ziepert, PhD
Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
Fazila Asmar, MD
Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Surgical and Molecular Pathology, National Tumour Biology Laboratory, National Institute of Oncology, Budapest, Hungary
Thomas Weber, MD
Department of Internal Medicine IV, Haematology and Oncology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
Rose-Marie Amini, MD, PhD https://orcid.org/0000-0003-0901-5252
Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden
Wolfram Klapper, MD
Department of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany
Maria Bouzani, MD
Department of Hematology and Lymphoma, BMTU, Evaggelismos General Hospital, Athens, Greece
Viola Poeschel, MD
Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical School, Homburg, Germany
Andreas Rosenwald, MD
Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
Gerhard Held, MD
Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical School, Homburg, Germany
Department Internal Medicine I, Westpfalzklinikum Kaiserslautern, Kaiserslautern, Germany
Centro de Investigacion Biomedica en Red en Oncologia (CIBERONC), Madrid, Spain
Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Naveed Ishaque, PhD
Berlin Institute of Health at Charité—Universitätsmedizin Berlin, Center of Digital Health, Berlin, Germany
Kostas Stamatopoulos, MD, PhD
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
George Kanellis, MD
Department of Hematopathology, Evangelismos General Hospital, Athens, Greece
Ioannis Anagnostopoulos, MD
Institute of Pathology, University of Würzburg and Comprehensive Cancer Center (CCC) Mainfranken, Würzburg, Germany
Department of Pathology, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
Neta Goldschmidt, MD
Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Pier Luigi Zinzani, MD, PhD https://orcid.org/0000-0002-2112-2651
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli,” Bologna, Italy
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
HCEMM-SE Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
Richard Rosenquist, MD, PhD https://orcid.org/0000-0002-0211-8788
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Theodoros P. Vassilakopoulos, MD, PhD https://orcid.org/0000-0001-8766-1853
Department of Internal Medicine IV, Haematology and Oncology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
Department of Hematology and Bone Marrow Transplantation, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Department of Medicine, Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan
Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

Notes

Frederik Damm, MD, Department of Hematology, Oncology, and Cancer Immunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; e-mail: [email protected]
*
D.N., F.B. and C.H. contributed equally as first authors to this work.

Author Contributions

Conception and design: Daniel Noerenberg, Franziska Briest, Seishi Ogawa, Frederik Damm
Financial support: Frederik Damm
Administrative support: Frederik Damm
Provision of study materials or patients: Annette M. Staiger, Erika Toth, Thomas Weber, Rose-Marie Amini, Maria Bouzani, Viola Poeschel, Andreas Rosenwald, Gerhard Held, Elías Campo, Ioannis Anagnostopoulos, Lars Bullinger, Pier Luigi Zinzani, Csaba Bödör, German Ott, Seishi Ogawa, Frederik Damm
Collection and assembly of data: Daniel Noerenberg, Franziska Briest, Cornelius Hennch, Yasuhide Takeuchi, Hiroo Ueno, Annette M. Staiger, Marita Ziepert, Fazila Asmar, Benjamin N. Locher, Erika Toth, Thomas Weber, Rose-Marie Amini, Maria Bouzani, Viola Poeschel, Andreas Rosenwald, Gerhard Held, Elías Campo, Kostas Stamatopoulos, Ioannis Anagnostopoulos, Lars Bullinger, Neta Goldschmidt, Csaba Bödör, Richard Rosenquist, Theodoros P. Vassilakopoulos, German Ott, Seishi Ogawa, Frederik Damm
Data analysis and interpretation: Daniel Noerenberg, Franziska Briest, Cornelius Hennch, Kenichi Yoshida, Raphael Hablesreiter, Yasuhide Takeuchi, Wolfram Klapper, Andreas Rosenwald, Naveed Ishaque, Kostas Stamatopoulos, Pier Luigi Zinzani, Csaba Bödör, Seishi Ogawa, Frederik Damm
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

Metrics & Citations

Metrics

Altmetric

Citations

Article Citation

Download Citation

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format





Download article citation data for:
Daniel Noerenberg, Franziska Briest, Cornelius Hennch, Kenichi Yoshida, Raphael Hablesreiter, Yasuhide Takeuchi, Hiroo Ueno, Annette M. Staiger, Marita Ziepert, Fazila Asmar, Benjamin N. Locher, Erika Toth, Thomas Weber, Rose-Marie Amini, Wolfram Klapper, Maria Bouzani, Viola Poeschel, Andreas Rosenwald, Gerhard Held, Elías Campo, Naveed Ishaque, Kostas Stamatopoulos, George Kanellis, Ioannis Anagnostopoulos, Lars Bullinger, Neta Goldschmidt, Pier Luigi Zinzani, Csaba Bödör, Richard Rosenquist, Theodoros P. Vassilakopoulos, German Ott, Seishi Ogawa, Frederik Damm
Journal of Clinical Oncology 2024 42:4, 452-466

View Options

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login

Purchase Options

Purchase this article to get full access to it.

Purchase this Article

Subscribe

Subscribe to this Journal
Renew Your Subscription
Become a Member

View options

View Full Text HTML

View Full Text HTML

PDF

View PDF

Media

Figures

Other

Tables

Share

Share

Share article link

Share