Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma.

Wojtek Drabarek,Annelies De Klein,Rick Jansen,Robert M Verdijk,Dion Paridaens,Bert Eussen,Job Van Riet,Natasha M Van Poppelen,Kyra N Smit,Jolanda Vaarwater,Tom Brands,Erwin Brosens,Thierry Van Den Bosch ,Nicole Naus ,Harmen J.g Van De Werken ,Eva Medico Salsench ,Frank Magielsen ,Emine Kılıç ,Josephine Q.n Nguyen ,Null Author_Id

doi:10.3390/cancers14030846

Wojtek Drabarek, Annelies De Klein + Show 18 more

Open Access

https://doi.org/10.3390/cancers14030846

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Abstract

Simple SummaryThis 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 (SF3B1mut) UM patients. We collected 146 SF3B1mut UM from our Rotterdam Ocular Melanoma Studygroup (ROMS) database and external published datasets. After stratification of all SF3B1mut 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 SF3B1mut 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 SF3B1mut-specific canonical transcripts (e.g., a low expression of ABHD6 indicative for early-onset metastatic disease) or distinct expression of SF3B1mut UM aberrant transcripts, indicative of early- or late-onset or no metastatic SF3B1mut UM.

Highlights

Uveal melanoma (UM) is a highly malignant tumor with metastatic capacity
One UM sample classified as SF3B1mut UM in the Yavuzyigitoglu et al set was excluded due to melanoma originating from Nevus of Ota
We hypothesized clinical or genetic variables could be indicative for either early-onset metastatic disease SF3B1mut UM (PFS < 60 months) or SF3B1mut UM patients with late-onset metastatic disease (PFS ≥ 60 months)