Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma

Simple Summary This study describes clinical and genetic characteristics of the largest aggregated cohort of Splicing Factor 3 Subunit B1 (SF3B1)-mutated Uveal Melanoma (UM) in the literature (n = 146). Missense mutations in the spliceosome gene SF3B1 result in an altered splice site recognition and aberrant mRNA transcripts. The SF3B1-mutated UM show early- and late-onset of metastatic disease for which, currently, no distinguishing biomarkers exist. Using a cutoff of 60 months for stratification, we found that a largest basal tumor diameter was more prevalent in the early-onset metastatic disease group. Furthermore, using differential gene expression and the detection of aberrant transcripts, we found that the expression of alpha/beta-Hydrolase domain containing 6 (ABHD6) is associated with early-onset metastatic SF3B1 and aberrant transcripts that are associated with early-onset SF3B1-mutated UM. Our results provide more accurate prognostication and targets for future functional studies in an effort to elucidate pathogenesis of SF3B1-mutated UM. Approximately 25% of all uveal melanoma (UM) contain driver mutations in the gene encoding the spliceosome factor SF3B1, and whilst patients with such SF3B1 mutations generally have an intermediate risk on developing metastatic disease, a third of these patients develop early metastasis within 5 years after diagnosis. We therefore investigated whether clinical and/or genetic variables could be indicative of short progression-free survival (PFS < 60 months) or long PFS (PFS >= 60 months) for SF3B1-mutated (SF3B1(mut)) UM patients. We collected 146 SF3B1(mut) UM from our Rotterdam Ocular Melanoma Studygroup (ROMS) database and external published datasets. After stratification of all SF3B1(mut) UM using short PFS vs. long PFS, only largest tumor diameter (LTD) was significantly larger (mean: 17.7 mm (+/- 2.8 SD) in the short PFS SF3B1(mut) group vs. the long PFS group (mean: 14.7 (+/- 3.7 SD, p = 0.001). Combined ROMS and The Cancer Genome Atlas (TCGA) transcriptomic data were evaluated, and we identified SF3B1(mut)-specific canonical transcripts (e.g., a low expression of ABHD6 indicative for early-onset metastatic disease) or distinct expression of SF3B1(mut) UM aberrant transcripts, indicative of early- or late-onset or no metastatic SF3B1(mut) UM.

Automated summary

This study describes the clinical and genetic characteristics of a cohort of 146 SF3B1-mutated UM, finding that SF3B1-mutated UM exhibit early- and late-onset metastatic disease without distinguishing biomarkers, with largest basal tumor diameter possibly associated with early metastasis. Analysis of gene expression and aberrant transcripts revealed an association between ABHD6 expression and early-onset metastatic SF3B1, providing potential prognostic indicators and therapeutic targets for SF3B1-mutated UM.