Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-31866-4
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Funding
- NCT Molecular Precision Oncology Program
- DKFZ-Heidelberg Center for Personalized Oncology [H021]
- DKTK Joint Funding Program
- German Academic Scholarship Foundation (Studienstiftung des deutschen Volkes)
- Heinrich-Boell-Foundation
- Else Kroner Research College Dresden
- Clinician Scientist Program of the University Medicine Essen Clinician Scientist Academy (UMEA) - faculty of medicine
- Deutsche Forschungsgemeinschaft (DFG)
- Mildred-Scheel-Professorship Program of the German Cancer Aid [70114112]
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We conducted comprehensive molecular characterization of 70 patients with cancer of unknown primary and identified substantial mutational heterogeneity and commonly mutated cancer-related genes. Our data demonstrate the clinical value of molecular analysis and recommend off-label therapy for a subset of patients, resulting in improved progression-free survival.
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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