Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity

Lino Möhrmann, Maximilian Werner, Małgorzata Oleś, Andreas Mock, Sebastian Uhrig, Arne Jahn, Simon Kreutzfeldt, Martina Fröhlich, Barbara Hutter, Nagarajan Paramasivam, Daniela Richter, Katja Beck, Ulrike Winter, Katrin Pfütze, Christoph E. Heilig, Veronica Teleanu, Daniel B. Lipka, Marc Zapatka, Dorothea Hanf, Catrin List, Michael Allgäuer, Roland Penzel, Gina Rüter, Ivan Jelas, Rainer Hamacher, Johanna Falkenhorst, Sebastian Wagner, Christian H. Brandts, Melanie Boerries, Anna L. Illert, Klaus H. Metzeler, C. Benedikt Westphalen, Alexander Desuki, Thomas Kindler, Gunnar Folprecht, Wilko Weichert, Benedikt Brors, Albrecht Stenzinger, Evelin Schröck, Daniel Hübschmann, Peter Horak, Christoph Heining, Stefan Fröhling and Hanno Glimm ()
Additional contact information
Lino Möhrmann: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
Maximilian Werner: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
Małgorzata Oleś: Computational Oncology Group, NCT Heidelberg and DKFZ
Andreas Mock: NCT Heidelberg and DKFZ
Sebastian Uhrig: Computational Oncology Group, NCT Heidelberg and DKFZ
Arne Jahn: NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
Simon Kreutzfeldt: NCT Heidelberg and DKFZ
Martina Fröhlich: Computational Oncology Group, NCT Heidelberg and DKFZ
Barbara Hutter: Computational Oncology Group, NCT Heidelberg and DKFZ
Nagarajan Paramasivam: Computational Oncology Group, NCT Heidelberg and DKFZ
Daniela Richter: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
Katja Beck: Molecular Precision Oncology Program, NCT Heidelberg
Ulrike Winter: Molecular Precision Oncology Program, NCT Heidelberg
Katrin Pfütze: Molecular Precision Oncology Program, NCT Heidelberg
Christoph E. Heilig: NCT Heidelberg and DKFZ
Veronica Teleanu: NCT Heidelberg and DKFZ
Daniel B. Lipka: NCT Heidelberg and DKFZ
Marc Zapatka: Division of Molecular Genetics, DKFZ
Dorothea Hanf: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
Catrin List: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
Michael Allgäuer: University Hospital Heidelberg
Roland Penzel: University Hospital Heidelberg
Gina Rüter: Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin
Ivan Jelas: Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin
Rainer Hamacher: West German Cancer Center, University Hospital Essen
Johanna Falkenhorst: West German Cancer Center, University Hospital Essen
Sebastian Wagner: Hematology/Oncology, Goethe University
Christian H. Brandts: Hematology/Oncology, Goethe University
Melanie Boerries: Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg
Anna L. Illert: DKTK
Klaus H. Metzeler: University Hospital, LMU Munich and Comprehensive Cancer Center
C. Benedikt Westphalen: University Hospital, LMU Munich and Comprehensive Cancer Center
Alexander Desuki: University Cancer Center Mainz, University Medical Center Mainz
Thomas Kindler: University Cancer Center Mainz, University Medical Center Mainz
Gunnar Folprecht: NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
Wilko Weichert: Technical University Munich
Benedikt Brors: NCT Heidelberg and DKFZ
Albrecht Stenzinger: University Hospital Heidelberg
Evelin Schröck: NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
Daniel Hübschmann: Computational Oncology Group, NCT Heidelberg and DKFZ
Peter Horak: NCT Heidelberg and DKFZ
Christoph Heining: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
Stefan Fröhling: NCT Heidelberg and DKFZ
Hanno Glimm: National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The benefit of molecularly-informed therapies in cancer of unknown primary (CUP) is unclear. Here, we use comprehensive molecular characterization by whole genome/exome, transcriptome and methylome analysis in 70 CUP patients to reveal substantial mutational heterogeneity with TP53, MUC16, KRAS, LRP1B and CSMD3 being the most frequently mutated known cancer-related genes. The most common fusion partner is FGFR2, the most common focal homozygous deletion affects CDKN2A. 56/70 (80%) patients receive genomics-based treatment recommendations which are applied in 20/56 (36%) cases. Transcriptome and methylome data provide evidence for the underlying entity in 62/70 (89%) cases. Germline analysis reveals five (likely) pathogenic mutations in five patients. Recommended off-label therapies translate into a mean PFS ratio of 3.6 with a median PFS1 of 2.9 months (17 patients) and a median PFS2 of 7.8 months (20 patients). Our data emphasize the clinical value of molecular analysis and underline the need for innovative, mechanism-based clinical trials.

Date: 2022
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DOI: 10.1038/s41467-022-31866-4

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