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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Detalles Bibliográficos
Autores principales: Möhrmann, Lino, Werner, Maximilian, Oleś, Małgorzata, Mock, Andreas, Uhrig, Sebastian, Jahn, Arne, Kreutzfeldt, Simon, Fröhlich, Martina, Hutter, Barbara, Paramasivam, Nagarajan, Richter, Daniela, Beck, Katja, Winter, Ulrike, Pfütze, Katrin, Heilig, Christoph E., Teleanu, Veronica, Lipka, Daniel B., Zapatka, Marc, Hanf, Dorothea, List, Catrin, Allgäuer, Michael, Penzel, Roland, Rüter, Gina, Jelas, Ivan, Hamacher, Rainer, Falkenhorst, Johanna, Wagner, Sebastian, Brandts, Christian H., Boerries, Melanie, Illert, Anna L., Metzeler, Klaus H., Westphalen, C. Benedikt, Desuki, Alexander, Kindler, Thomas, Folprecht, Gunnar, Weichert, Wilko, Brors, Benedikt, Stenzinger, Albrecht, Schröck, Evelin, Hübschmann, Daniel, Horak, Peter, Heining, Christoph, Fröhling, Stefan, Glimm, Hanno
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9346116/
https://www.ncbi.nlm.nih.gov/pubmed/35918329
http://dx.doi.org/10.1038/s41467-022-31866-4
Descripción
Sumario: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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