Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling
Parathyroid carcinoma (PC) is an ultra‐rare malignancy with a high risk of recurrence after surgery. Tumour‐directed systemic treatments for PC are not established. We used whole‐genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical m...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-07-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13398 |
| _version_ | 1827906882023456768 |
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| author | Maria‐Veronica Teleanu Carmina T. Fuss Nagarajan Paramasivam Sebastian Pirmann Andreas Mock Christoph Terkamp Stefan Kircher Laura‐Sophie Landwehr Christina Lenschow Nicolas Schlegel Albrecht Stenzinger Arne Jahn Martin Fassnacht Hanno Glimm Daniel Hübschmann Stefan Fröhling Matthias Kroiss |
| author_facet | Maria‐Veronica Teleanu Carmina T. Fuss Nagarajan Paramasivam Sebastian Pirmann Andreas Mock Christoph Terkamp Stefan Kircher Laura‐Sophie Landwehr Christina Lenschow Nicolas Schlegel Albrecht Stenzinger Arne Jahn Martin Fassnacht Hanno Glimm Daniel Hübschmann Stefan Fröhling Matthias Kroiss |
| author_sort | Maria‐Veronica Teleanu |
| collection | DOAJ |
| description | Parathyroid carcinoma (PC) is an ultra‐rare malignancy with a high risk of recurrence after surgery. Tumour‐directed systemic treatments for PC are not established. We used whole‐genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single‐base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like) overactivation; (b) multi‐receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto‐Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP‐Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome‐wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra‐rare cancers based on insight into disease biology. |
| first_indexed | 2024-03-13T01:03:00Z |
| format | Article |
| id | doaj.art-65702defbecb40ad800aa40dca446c3b |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-13T01:03:00Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-65702defbecb40ad800aa40dca446c3b2023-07-06T09:54:22ZengWileyMolecular Oncology1574-78911878-02612023-07-011771343135510.1002/1878-0261.13398Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profilingMaria‐Veronica Teleanu0Carmina T. Fuss1Nagarajan Paramasivam2Sebastian Pirmann3Andreas Mock4Christoph Terkamp5Stefan Kircher6Laura‐Sophie Landwehr7Christina Lenschow8Nicolas Schlegel9Albrecht Stenzinger10Arne Jahn11Martin Fassnacht12Hanno Glimm13Daniel Hübschmann14Stefan Fröhling15Matthias Kroiss16Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg German Cancer Research Center (DKFZ) Heidelberg GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital University of Würzburg GermanyComputational Oncology Group, Molecular Precision Oncology Program NCT Heidelberg and DKFZ GermanyComputational Oncology Group, Molecular Precision Oncology Program NCT Heidelberg and DKFZ GermanyDivision of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg German Cancer Research Center (DKFZ) Heidelberg GermanyDepartment of Gastroenterology, Hepatology and Endocrinology Hannover Medical School GermanyInstitute of Pathology University of Würzburg GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital University of Würzburg GermanyDepartment of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital University of Würzburg GermanyDepartment of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital University of Würzburg GermanyInstitute of Pathology Heidelberg University Hospital GermanyInstitute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus Technische Universität Dresden GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital University of Würzburg GermanyDepartment of Translational Medical Oncology National Center for Tumor Diseases (NCT/UCC) Dresden GermanyComputational Oncology Group, Molecular Precision Oncology Program NCT Heidelberg and DKFZ GermanyDivision of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg German Cancer Research Center (DKFZ) Heidelberg GermanyDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital University of Würzburg GermanyParathyroid carcinoma (PC) is an ultra‐rare malignancy with a high risk of recurrence after surgery. Tumour‐directed systemic treatments for PC are not established. We used whole‐genome and RNA sequencing in four patients with advanced PC to identify molecular alterations that could guide clinical management. In two cases, the genomic and transcriptomic profiles provided targets for experimental therapies that resulted in biochemical response and prolonged disease stabilization: (a) immune checkpoint inhibition with pembrolizumab based on high tumour mutational burden and a single‐base substitution signature associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like) overactivation; (b) multi‐receptor tyrosine kinase inhibition with lenvatinib due to overexpression of FGFR1 (Fibroblast Growth Factor Receptor 1) and RET (Ret Proto‐Oncogene) and, (c) later in the course of the disease, PARP (Poly(ADP‐Ribose) Polymerase) inhibition with olaparib prompted by signs of defective homologous recombination DNA repair. In addition, our data provided new insights into the molecular landscape of PC with respect to the genome‐wide footprints of specific mutational processes and pathogenic germline alterations. These data underscore the potential of comprehensive molecular analyses to improve care for patients with ultra‐rare cancers based on insight into disease biology.https://doi.org/10.1002/1878-0261.13398immune checkpoint inhibitionmutational signatureRNA sequencingtumour mutational burdentyrosine kinase inhibitionwhole‐genome sequencing |
| spellingShingle | Maria‐Veronica Teleanu Carmina T. Fuss Nagarajan Paramasivam Sebastian Pirmann Andreas Mock Christoph Terkamp Stefan Kircher Laura‐Sophie Landwehr Christina Lenschow Nicolas Schlegel Albrecht Stenzinger Arne Jahn Martin Fassnacht Hanno Glimm Daniel Hübschmann Stefan Fröhling Matthias Kroiss Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling Molecular Oncology immune checkpoint inhibition mutational signature RNA sequencing tumour mutational burden tyrosine kinase inhibition whole‐genome sequencing |
| title | Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling |
| title_full | Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling |
| title_fullStr | Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling |
| title_full_unstemmed | Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling |
| title_short | Targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling |
| title_sort | targeted therapy of advanced parathyroid carcinoma guided by genomic and transcriptomic profiling |
| topic | immune checkpoint inhibition mutational signature RNA sequencing tumour mutational burden tyrosine kinase inhibition whole‐genome sequencing |
| url | https://doi.org/10.1002/1878-0261.13398 |
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