Metastasis-related genomic aberrations and evolutionary trajectory in uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular cancer, characterized by genetic variations associated with metastasis-related mortality. Current prognostic classifications primarily rely on large-scale copy number alterations without incorporating more precise genomic aberrations. We present a comprehensive analysis of whole-genome sequences from 40 primary UMs and matched normal tissues, revealing a complete landscape of somatic aberrations, including loss of heterozygosity and structural variations. It enabled the identification of two novel metastatic markers: BAP1 aberrations (including loss of heterozygosity and structural variation-associated truncations, which were not revealed by previous targeted approaches) and 1q gains, thereby enhancing current molecular stratification for metastatic risk. Mutation timing analysis revealed that prevalent copy gains were often acquired early in life, several decades before tumour diagnosis. Notably, early 6p gain was frequently exclusive of BAP1 aberrations and associated with a favourable prognosis, suggesting that metastatic potential in UM may be established early during tumorigenesis. Collectively, our findings provide molecular changes contributing to tumorigenesis and metastatic progression in UM and offer potential biomarkers for early detection and prognosis prediction.