Molecular determinants of survival in metastatic uveal melanoma: The impact of SF3B1 mutations

Abstract

Purpose: To determine whether key molecular alterations in primary uveal melanoma (UM), including mutations and somatic copy number alterations (SCNAs), serve as prognostic markers in metastatic UM (MUM). Experimental design: Retrospective analysis of a prospective cohort study of clinical and molecular data from UM and MUM patients. Results: A total of 220 patients with primary UM treated at Hospital de Bellvitge, including 79 (36 %) who developed metastases, primarily in the liver. Genetic analyses of primary tumors included hotspot mutation testing for GNAQ, GNA11, and SF3B1, along with SCNA assessment (chromosomes 3, 8, 1, and 6) via Multiplex Ligation-dependent Probe Amplification (MLPA). Kaplan-Meier and Cox proportional hazards models assessed the impact of genetic alterations on relapse-free survival (RFS) and overall survival (OS) . Results: Monosomy 3 (M3) and chromosome 8q amplification (8A) were associated with shorter RFS (p <0.0001) in primary UM but did not impact OS in MUM (p = 0.33). SF3B1 mutations (SF3B1m) conferred significantly longer OS in MUM (31.7 vs. 11.8 months, p = 0.001), independently confirmed in multivariate analysis (HR=0.26, p = 0.01), irrespective of tebentafusp treatment. Conclusions: Traditional chromosomal markers stratify primary UM but fail to predict OS in MUM. SF3B1m emerges as a novel prognostic factor, indicating a distinct biological phenotype with potential therapeutic implications. Further studies are warranted to validate its prognostic and therapeutic relevance in MUM.