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

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, LRP...

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Main Authors:	Möhrmann, Lino (Author) , Werner, Maximilian (Author) , Oleś, Małgorzata (Author) , Mock, Andreas (Author) , Uhrig, Sebastian (Author) , Jahn, Arne (Author) , Kreutzfeldt, Simon (Author) , Fröhlich, Martina (Author) , Hutter, Barbara (Author) , Paramasivam, Nagarajan (Author) , Richter, Daniela (Author) , Beck, Katja (Author) , Winter, Ulrike (Author) , Pfütze, Katrin (Author) , Heilig, Christoph E. (Author) , Teleanu, Maria-Veronica (Author) , Lipka, Daniel (Author) , Zapatka, Marc (Author) , Hanf, Dorothea (Author) , List, Catrin (Author) , Allgäuer, Michael (Author) , Penzel, Roland (Author) , Rüter, Gina (Author) , Jelas, Ivan (Author) , Hamacher, Rainer W. (Author) , Falkenhorst, Johanna (Author) , Wagner, Sebastian (Author) , Brandts, Christian H. (Author) , Börries, Melanie (Author) , Illert, Anna Lena (Author) , Metzeler, Klaus H. (Author) , Westphalen, C. Benedikt (Author) , Desuki, Alexander (Author) , Kindler, Thomas (Author) , Folprecht, Gunnar (Author) , Weichert, Wilko (Author) , Brors, Benedikt (Author) , Stenzinger, Albrecht (Author) , Schröck, Evelin (Author) , Hübschmann, Daniel (Author) , Horak, Peter (Author) , Heining, Christoph (Author) , Fröhling, Stefan (Author) , Glimm, Hanno (Author)
Format:	Article (Journal)
Language:	English
Published:	02 August 2022
In:	Nature Communications Year: 2022, Volume: 13, Pages: 1-15
ISSN:	2041-1723
DOI:	10.1038/s41467-022-31866-4
Online Access:	Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-022-31866-4 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-022-31866-4
Author Notes:	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

MARC


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245	1	0	\|a Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity \|c 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
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520			\|a 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.
650		4	\|a Cancer genetics
650		4	\|a Cancer genomics
650		4	\|a Cancer of unknown primary
650		4	\|a Molecular medicine
650		4	\|a Translational research
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Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity

MARC

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