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

Author

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  • Lino Möhrmann

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
    German Cancer Consortium (DKTK))

  • Maximilian Werner

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ))

  • Małgorzata Oleś

    (Computational Oncology Group, NCT Heidelberg and DKFZ
    NCT Heidelberg and DKFZ)

  • Andreas Mock

    (NCT Heidelberg and DKFZ
    NCT Heidelberg and Heidelberg University Hospital)

  • Sebastian Uhrig

    (Computational Oncology Group, NCT Heidelberg and DKFZ
    Molecular Precision Oncology Program, NCT Heidelberg)

  • Arne Jahn

    (NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
    German Cancer Consortium (DKTK)
    University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden)

  • Simon Kreutzfeldt

    (NCT Heidelberg and DKFZ)

  • Martina Fröhlich

    (Computational Oncology Group, NCT Heidelberg and DKFZ
    Molecular Precision Oncology Program, NCT Heidelberg)

  • Barbara Hutter

    (Computational Oncology Group, NCT Heidelberg and DKFZ
    Molecular Precision Oncology Program, NCT Heidelberg)

  • Nagarajan Paramasivam

    (Computational Oncology Group, NCT Heidelberg and DKFZ
    Molecular Precision Oncology Program, NCT Heidelberg)

  • Daniela Richter

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    German Cancer Consortium (DKTK))

  • 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
    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)
    NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden)

  • Catrin List

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden)

  • 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
    DKTK)

  • Johanna Falkenhorst

    (West German Cancer Center, University Hospital Essen
    DKTK)

  • Sebastian Wagner

    (Hematology/Oncology, Goethe University
    DKTK)

  • Christian H. Brandts

    (Hematology/Oncology, Goethe University
    DKTK)

  • Melanie Boerries

    (Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg
    DKTK)

  • Anna L. Illert

    (DKTK
    Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg)

  • Klaus H. Metzeler

    (University Hospital, LMU Munich and Comprehensive Cancer Center
    University Hospital Leipzig)

  • C. Benedikt Westphalen

    (University Hospital, LMU Munich and Comprehensive Cancer Center)

  • Alexander Desuki

    (University Cancer Center Mainz, University Medical Center Mainz
    DKTK)

  • Thomas Kindler

    (University Cancer Center Mainz, University Medical Center Mainz
    DKTK)

  • 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
    German Cancer Consortium (DKTK)
    University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden)

  • Daniel Hübschmann

    (Computational Oncology Group, NCT Heidelberg and DKFZ
    Molecular Precision Oncology Program, NCT Heidelberg
    Pattern Recognition and Digital Medicine, Heidelberg Institute for Stem cell Technology and Experimental Medicine
    DKTK)

  • Peter Horak

    (NCT Heidelberg and DKFZ
    DKTK)

  • Christoph Heining

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
    German Cancer Consortium (DKTK))

  • Stefan Fröhling

    (NCT Heidelberg and DKFZ
    DKTK)

  • Hanno Glimm

    (National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ)
    NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden
    German Cancer Consortium (DKTK)
    Translational Functional Cancer Genomics, NCT Heidelberg and DKFZ)

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.

Suggested Citation

  • Lino Möhrmann & Maximilian Werner & Małgorzata Oleś & Andreas Mock & Sebastian Uhrig & Arne Jahn & Simon Kreutzfeldt & Martina Fröhlich & Barbara Hutter & Nagarajan Paramasivam & Daniela Richter & Kat, 2022. "Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31866-4
    DOI: 10.1038/s41467-022-31866-4
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