Biagio Ricciuti, Thoracic Medical Oncologist at Dana-Farber Cancer Institute, shared on LinkedIn:
“Excited to share our recent study, out now in Nature Genetics in which we identified associations between gene mutant dosage (GMD) and prognosis and metastatic tropism across 60,000 clinical cancer samples. Led by Giulio Caravagna, Nicola Calonaci and Eriseld Krasniqi with Marcello Maugeri-Saccà, Trevor Graham, Stefano Scalera, Daniel Colic and many others.
Clinical sequencing typically classifies tumors using binary mutation status. In this study, we evaluated gene mutant dosage (GMD), defined by the copy number and multiplicity of a somatic mutation.
Using INCOMMON, an open-source Bayesian framework we inferred GMD directly from tumor-only targeted sequencing data without requiring matched normal samples or controlled-access raw sequencing files.
Across more than 500,000 mutations in approximately 60,000 tumors GMD identified:
- 46 tumor-type-specific biomarkers associated with overall survival
- 26 biomarkers associated with metastatic dissemination
20 biomarkers associated with organ-specific metastatic tropism
Higher mutant dosage across the RAS/RAF pathway, including KRAS, NRAS, and BRAF, was consistently associated with worse outcomes in several tumor types. Additional dosage-dependent associations involved PIK3CA, TP53, STK11, TERT, and EGFR.
These findings support incorporating mutation copy number and allelic configuration into genomic biomarker analyses rather than relying exclusively on binary mutation status.
INCOMMON.”
Title: Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples
Authors: Nicola Calonaci, Eriseld Krasniqi, Daniel Colic, Stefano Scalera, Giorgia Gandolfi, Salvatore Milite, Konstantin Bräutigam, Andrea Sottoriva, Trevor A. Graham, Leonardo Egidi, Biagio Ricciuti, Marcello Maugeri-Saccà, Giulio Caravagna
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