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

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 ListMichael 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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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.

Original language	English
Article number	4485
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31866-4
State	Published - Dec 2022

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10.1038/s41467-022-31866-4

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Möhrmann, L., Werner, M., Oleś, M., Mock, A., Uhrig, S., Jahn, A., Kreutzfeldt, S., Fröhlich, M., Hutter, B., Paramasivam, N., Richter, D., Beck, K., Winter, U., Pfütze, K., Heilig, C. E., Teleanu, V., Lipka, D. B., Zapatka, M., Hanf, D., ... Glimm, H. (2022). Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity. Nature Communications, 13(1), Article 4485. https://doi.org/10.1038/s41467-022-31866-4

@article{6a43cae0912a4c7194392015c2920662,

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

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.",

author = "Lino M{\"o}hrmann and Maximilian Werner and Ma{\l}gorzata Ole{\'s} and Andreas Mock and Sebastian Uhrig and Arne Jahn and Simon Kreutzfeldt and Martina Fr{\"o}hlich and Barbara Hutter and Nagarajan Paramasivam and Daniela Richter and Katja Beck and Ulrike Winter and Katrin Pf{\"u}tze and Heilig, {Christoph E.} and Veronica Teleanu and Lipka, {Daniel B.} and Marc Zapatka and Dorothea Hanf and Catrin List and Michael Allg{\"a}uer and Roland Penzel and Gina R{\"u}ter and Ivan Jelas and Rainer Hamacher and Johanna Falkenhorst and Sebastian Wagner and Brandts, {Christian H.} and Melanie Boerries and Illert, {Anna L.} and Metzeler, {Klaus H.} and Westphalen, {C. Benedikt} and Alexander Desuki and Thomas Kindler and Gunnar Folprecht and Wilko Weichert and Benedikt Brors and Albrecht Stenzinger and Evelin Schr{\"o}ck and Daniel H{\"u}bschmann and Peter Horak and Christoph Heining and Stefan Fr{\"o}hling and Hanno Glimm",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-31866-4",

language = "English",

volume = "13",

journal = "Nature Communications",

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Möhrmann, L, Werner, M, Oleś, M, Mock, A, Uhrig, S, Jahn, A, Kreutzfeldt, S, Fröhlich, M, Hutter, B, Paramasivam, N, Richter, D, Beck, K, Winter, U, Pfütze, K, Heilig, CE, Teleanu, V, Lipka, DB, Zapatka, M, Hanf, D, List, C, Allgäuer, M, Penzel, R, Rüter, G, Jelas, I, Hamacher, R, Falkenhorst, J, Wagner, S, Brandts, CH, Boerries, M, Illert, AL, Metzeler, KH, Westphalen, CB, Desuki, A, Kindler, T, Folprecht, G, Weichert, W, Brors, B, Stenzinger, A, Schröck, E, Hübschmann, D, Horak, P, Heining, C, Fröhling, S & Glimm, H 2022, 'Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity', Nature Communications, vol. 13, no. 1, 4485. https://doi.org/10.1038/s41467-022-31866-4

TY - JOUR

T1 - Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity

AU - Möhrmann, Lino

AU - Werner, Maximilian

AU - Oleś, Małgorzata

AU - Mock, Andreas

AU - Uhrig, Sebastian

AU - Jahn, Arne

AU - Kreutzfeldt, Simon

AU - Fröhlich, Martina

AU - Hutter, Barbara

AU - Paramasivam, Nagarajan

AU - Richter, Daniela

AU - Beck, Katja

AU - Winter, Ulrike

AU - Pfütze, Katrin

AU - Heilig, Christoph E.

AU - Teleanu, Veronica

AU - Lipka, Daniel B.

AU - Zapatka, Marc

AU - Hanf, Dorothea

AU - List, Catrin

AU - Allgäuer, Michael

AU - Penzel, Roland

AU - Rüter, Gina

AU - Jelas, Ivan

AU - Hamacher, Rainer

AU - Falkenhorst, Johanna

AU - Wagner, Sebastian

AU - Brandts, Christian H.

AU - Boerries, Melanie

AU - Illert, Anna L.

AU - Metzeler, Klaus H.

AU - Westphalen, C. Benedikt

AU - Desuki, Alexander

AU - Kindler, Thomas

AU - Folprecht, Gunnar

AU - Weichert, Wilko

AU - Brors, Benedikt

AU - Stenzinger, Albrecht

AU - Schröck, Evelin

AU - Hübschmann, Daniel

AU - Horak, Peter

AU - Heining, Christoph

AU - Fröhling, Stefan

AU - Glimm, Hanno

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-022-31866-4

DO - 10.1038/s41467-022-31866-4

M3 - Article

C2 - 35918329

AN - SCOPUS:85135257212

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4485

ER -

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

Abstract

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