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.

The identification of molecular biomarkers in cancer of unknown primary site (CUP) cases may enable the improvement of prognosis in these patients. Here, the authors integrate whole genome/exome, transcriptome and methylome data in 70 CUP patients, recommend therapies based on their analysis and report clinical outcome data.

Details

Title
Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity
Author
Möhrmann, Lino 1   VIAFID ORCID Logo  ; Werner, Maximilian 2   VIAFID ORCID Logo  ; Oleś, Małgorzata 3   VIAFID ORCID Logo  ; Mock, Andreas 4   VIAFID ORCID Logo  ; Uhrig, Sebastian 5 ; Jahn, Arne 6   VIAFID ORCID Logo  ; Kreutzfeldt, Simon 7   VIAFID ORCID Logo  ; Fröhlich, Martina 5 ; Hutter, Barbara 5   VIAFID ORCID Logo  ; Paramasivam, Nagarajan 5 ; Richter, Daniela 8 ; Beck, Katja 9 ; Winter, Ulrike 9 ; Pfütze, Katrin 9 ; Heilig, Christoph E. 7   VIAFID ORCID Logo  ; Teleanu, Veronica 7 ; Lipka, Daniel B. 10   VIAFID ORCID Logo  ; Zapatka, Marc 11 ; Hanf, Dorothea 12 ; List, Catrin 12 ; Allgäuer, Michael 13   VIAFID ORCID Logo  ; Penzel, Roland 13 ; Rüter, Gina 14 ; Jelas, Ivan 14 ; Hamacher, Rainer 15   VIAFID ORCID Logo  ; Falkenhorst, Johanna 15 ; Wagner, Sebastian 16 ; Brandts, Christian H. 16 ; Boerries, Melanie 17   VIAFID ORCID Logo  ; Illert, Anna L. 18 ; Metzeler, Klaus H. 19   VIAFID ORCID Logo  ; Westphalen, C. Benedikt 20 ; Desuki, Alexander 21 ; Kindler, Thomas 21 ; Folprecht, Gunnar 22 ; Weichert, Wilko 23 ; Brors, Benedikt 24   VIAFID ORCID Logo  ; Stenzinger, Albrecht 13 ; Schröck, Evelin 6 ; Hübschmann, Daniel 25   VIAFID ORCID Logo  ; Horak, Peter 26   VIAFID ORCID Logo  ; Heining, Christoph 1 ; Fröhling, Stefan 26   VIAFID ORCID Logo  ; Glimm, Hanno 27   VIAFID ORCID Logo 

1  National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Center for Personalized Oncology, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257); German Cancer Consortium (DKTK), Dresden, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
2  National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
3  Computational Oncology Group, NCT Heidelberg and DKFZ, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); NCT Heidelberg and DKFZ, Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
4  NCT Heidelberg and DKFZ, Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); NCT Heidelberg and Heidelberg University Hospital, Department of Medical Oncology, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
5  Computational Oncology Group, NCT Heidelberg and DKFZ, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); Molecular Precision Oncology Program, NCT Heidelberg, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
6  NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Center for Personalized Oncology, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257); German Cancer Consortium (DKTK), Dresden, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Institute for Clinical Genetics, Dresden, Germany (GRID:grid.412282.f) (ISNI:0000 0001 1091 2917) 
7  NCT Heidelberg and DKFZ, Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
8  National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); German Cancer Consortium (DKTK), Dresden, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
9  Molecular Precision Oncology Program, NCT Heidelberg, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
10  NCT Heidelberg and DKFZ, Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); NCT Heidelberg and DKFZ, Section Translational Cancer Epigenomics, Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
11  Division of Molecular Genetics, DKFZ, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
12  National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Center for Personalized Oncology, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257) 
13  University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany (GRID:grid.5253.1) (ISNI:0000 0001 0328 4908) 
14  Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany (GRID:grid.6363.0) (ISNI:0000 0001 2218 4662) 
15  West German Cancer Center, University Hospital Essen, Department of Medical Oncology, Essen, Germany (GRID:grid.410718.b) (ISNI:0000 0001 0262 7331); DKTK, Essen, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
16  Hematology/Oncology, Goethe University, Department of Medicine 2, Frankfurt, Germany (GRID:grid.7839.5) (ISNI:0000 0004 1936 9721); DKTK, Frankfurt, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
17  Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Institute of Medical Bioinformatics and Systems Medicine, Freiburg im Breisgau, Germany (GRID:grid.7708.8) (ISNI:0000 0000 9428 7911); DKTK, Freiburg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
18  DKTK, Freiburg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Department of Internal Medicine I, Freiburg, Germany (GRID:grid.7708.8) (ISNI:0000 0000 9428 7911) 
19  University Hospital, LMU Munich and Comprehensive Cancer Center, Department of Internal Medicine III, Munich, Germany (GRID:grid.411095.8) (ISNI:0000 0004 0477 2585); University Hospital Leipzig, Department of Hematology and Cellular Therapy, Leipzig, Germany (GRID:grid.411339.d) (ISNI:0000 0000 8517 9062) 
20  University Hospital, LMU Munich and Comprehensive Cancer Center, Department of Internal Medicine III, Munich, Germany (GRID:grid.411095.8) (ISNI:0000 0004 0477 2585) 
21  University Cancer Center Mainz, University Medical Center Mainz, Mainz, Germany (GRID:grid.5802.f) (ISNI:0000 0001 1941 7111); DKTK, Mainz, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
22  NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Center for Personalized Oncology, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257) 
23  Technical University Munich, Institute of Pathology, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
24  NCT Heidelberg and DKFZ, Division of Applied Bioinformatics, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
25  Computational Oncology Group, NCT Heidelberg and DKFZ, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); Molecular Precision Oncology Program, NCT Heidelberg, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); Pattern Recognition and Digital Medicine, Heidelberg Institute for Stem cell Technology and Experimental Medicine, Heidelberg, Germany (GRID:grid.482664.a); DKTK, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
26  NCT Heidelberg and DKFZ, Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); DKTK, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
27  National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Department of Translational Medical Oncology, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365); NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Center for Personalized Oncology, Dresden, Germany (GRID:grid.4488.0) (ISNI:0000 0001 2111 7257); German Cancer Consortium (DKTK), Dresden, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Translational Functional Cancer Genomics, NCT Heidelberg and DKFZ, Heidelberg, Germany (GRID:grid.461742.2) (ISNI:0000 0000 8855 0365) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-31866-4
ProQuest document ID
2697205379
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.