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; Hanno Glimm

doi:10.1038/s41467-022-31866-4

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

Nat Commun. 2022 Aug 2;13(1):4485. doi: 10.1038/s41467-022-31866-4.

Authors

Lino Möhrmann^#^{1

2

3}, Maximilian Werner^#¹, Małgorzata Oleś^#^{4

5}, Andreas Mock^#^{5

6}, Sebastian Uhrig^#^{4

7}, Arne Jahn^{2

3

8}, Simon Kreutzfeldt⁵, Martina Fröhlich^{4

7}, Barbara Hutter^{4

7}, Nagarajan Paramasivam^{4

7}, Daniela Richter^{1

3}, Katja Beck⁷, Ulrike Winter⁷, Katrin Pfütze⁷, Christoph E Heilig⁵, Veronica Teleanu⁵, Daniel B Lipka^{5

9}, Marc Zapatka¹⁰, Dorothea Hanf^{1

2}, Catrin List^{1

2}, Michael Allgäuer¹¹, Roland Penzel¹¹, Gina Rüter¹², Ivan Jelas¹², Rainer Hamacher^{13

14}, Johanna Falkenhorst^{13

14}, Sebastian Wagner^{15

16}, Christian H Brandts^{15

16}, Melanie Boerries^{17

18}, Anna L Illert^{18

19}, Klaus H Metzeler^{20

21}, C Benedikt Westphalen²⁰, Alexander Desuki^{22

23}, Thomas Kindler^{22

23}, Gunnar Folprecht², Wilko Weichert²⁴, Benedikt Brors²⁵, Albrecht Stenzinger¹¹, Evelin Schröck^{2

3

8}, Daniel Hübschmann^{4

7

26

27}, Peter Horak^{5

27}, Christoph Heining^{1

2

3}, Stefan Fröhling^{5

27}, Hanno Glimm^{28

29

30

31}

Affiliations

¹ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Dresden, Germany.
³ German Cancer Consortium (DKTK), Dresden, Germany.
⁴ Computational Oncology Group, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁵ Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁶ Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
⁷ Molecular Precision Oncology Program, NCT Heidelberg, Heidelberg, Germany.
⁸ Institute for Clinical Genetics, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, Dresden, Germany.
⁹ Section Translational Cancer Epigenomics, Department of Translational Medical Oncology, NCT Heidelberg and DKFZ, Heidelberg, Germany.
¹⁰ Division of Molecular Genetics, DKFZ, Heidelberg, Germany.
¹¹ Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
¹² Charité Comprehensive Cancer Center, Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
¹³ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
¹⁴ DKTK, Essen, Germany.
¹⁵ Department of Medicine 2, Hematology/Oncology, Goethe University, Frankfurt, Germany.
¹⁶ DKTK, Frankfurt, Germany.
¹⁷ Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
¹⁸ DKTK, Freiburg, Germany.
¹⁹ Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²⁰ Department of Internal Medicine III, University Hospital, LMU Munich and Comprehensive Cancer Center, Munich, Germany.
²¹ Department of Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany.
²² University Cancer Center Mainz, University Medical Center Mainz, Mainz, Germany.
²³ DKTK, Mainz, Germany.
²⁴ Institute of Pathology, Technical University Munich, Munich, Germany.
²⁵ Division of Applied Bioinformatics, NCT Heidelberg and DKFZ, Heidelberg, Germany.
²⁶ Pattern Recognition and Digital Medicine, Heidelberg Institute for Stem cell Technology and Experimental Medicine, Heidelberg, Germany.
²⁷ DKTK, Heidelberg, Germany.
²⁸ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
²⁹ Center for Personalized Oncology, NCT Dresden and University Hospital Carl Gustav Carus, Faculty of Medicine and Technische Universität Dresden, Dresden, Germany. [email protected].
³⁰ German Cancer Consortium (DKTK), Dresden, Germany. [email protected].
³¹ Translational Functional Cancer Genomics, NCT Heidelberg and DKFZ, Heidelberg, Germany. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Epigenomics
Genomics
Homozygote
Humans
Mutation
Neoplasms, Unknown Primary* / drug therapy
Neoplasms, Unknown Primary* / genetics
Sequence Deletion