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

Möhrmann, Lino; Werner, Maximilian; Oles, Malgorzata; 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; Ruter, 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; Schroeck, Evelin; Huebschmann, Daniel; Horak, Peter; Heining, Christoph; Froehling, Stefan und Glimm, Hanno (2022): Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly- informed therapies despite heterogeneity. In: Nature Communications, Bd. 13, Nr. 1, 4485

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch