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<p>The interplay between somatic mutations and copy number alterations influences tumor evolution and prognosis. These alterations are often treated independently, overlooking gene mutant dosage (GMD)—a key property of their interaction. Here we develop a computational framework that infers mutation copy number and multiplicity from targeted sequencing panels without requiring matched normal samples. We derive GMD for over 500,000 mutations across 60,000 pan-cancer samples. By stratifying more than 20,000 patients according to GMD across multiple genes, we identify 46 tumor-type-specific biomarkers predictive of survival, 13 of which were undetectable using binary mutant/wild-type models, 26 were associated with metastatic spread and 20 predicted metastatic tropism. Our method reveals GMD patterns as independent predictors of disease prognosis, metastatic potential and site-specific dissemination across diverse tumor types. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis and holds the potential to substantially enhance biomarker discovery.</p>

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Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月31日

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  • 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

摘要

The interplay between somatic mutations and copy number alterations influences tumor evolution and prognosis. These alterations are often treated independently, overlooking gene mutant dosage (GMD)—a key property of their interaction. Here we develop a computational framework that infers mutation copy number and multiplicity from targeted sequencing panels without requiring matched normal samples. We derive GMD for over 500,000 mutations across 60,000 pan-cancer samples. By stratifying more than 20,000 patients according to GMD across multiple genes, we identify 46 tumor-type-specific biomarkers predictive of survival, 13 of which were undetectable using binary mutant/wild-type models, 26 were associated with metastatic spread and 20 predicted metastatic tropism. Our method reveals GMD patterns as independent predictors of disease prognosis, metastatic potential and site-specific dissemination across diverse tumor types. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis and holds the potential to substantially enhance biomarker discovery.