Identification of Early-Onset Metastasis in SF3B1 Mutated Uveal Melanoma

Abstract

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.

Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma

“…Four of these ( ARMC9, ENOSF1, DPH5 and DLST ) have proven to be aberrantly spliced in SF3B1 MUT UM cell lines [9]. After re-analyzing the UM RNA-seq data of Wojtek et al[13], we included one additional gene CDK2 , and two control genes Charged Multivesicular Body Protein 2A ( CHMP2A ) and ER Membrane Protein Complex Subunit 7 ( EMC7 ). Results were analyzed using the image analysis software ImageQuantTL to determine the effect of E7107 on splicing inhibition in aberrant transcripts and canonical transcripts.…”

“…Prognostic factors include mutations in genes encoding BRCA1 associated protein 1 (BAP1) which has the worst prognosis, Splicing factor 3b Subunit 1 (SF3B1) with an intermediate prognosis, and Eukaryotic Translation Initiation Factor 1A X-Linked (EIF1AX) with the best prognosis [4,5]. Mutations in SF3B1 occur in approximately 15-25% of UM [6][7][8][9][10] and are associated with early-and late-onset metastasis [11][12][13]. Furthermore, SF3B1-mutated UM have a distinct copy number variation profile compared to other UM tumors, with more aberrations at the distal ends of chromosomes and frequently loss of chromosome 6q and gain of chromosome 6p and 8q [14].…”

Prognostic value of 8q gain in relation to BAP1 and SF3B1 mutated uveal melanoma

“…Whereas in BAP1 -mutated ( BAP1 MUT ) UM, gain of 8q is the result of whole chromosome 8 gain or the formation of isochromosome 8q, in case of SF3B1 -mutated ( SF3B1 MUT ) UM structural, often partial gain of 8q is predominant [3]. Some of these SF3B1 MUT UM patients develop early-onset metastatic disease [4], prompting to investigate the relationship between survival, gain of 8q and SF3B1 MUT UM.…”

“…Patients with SF3B1 MUT tumors (n=59) from the Rotterdam Ocular Melanoma Study group diagnosed between 1994 and 2022 were included in this study. CNVs were assessed using single nucleotide polymorphism (SNP) array (n=55) or in the past with karyotyping (n=17) and or fluorescence in situ hybridization (FISH, n=28) and when material was available used for transcriptome profiling (n=19) [4]. The summary plot showing the chromosomal patterns of the SNP arrays can be found in the supplementary (available at www.aaojournals.org).…”

“…The summary plot showing the chromosomal patterns of the SNP arrays can be found in the supplementary (available at www.aaojournals.org). Disease-free survival (DFS) was determined using a cut-off of 60 months to identify early-onset metastatic disease in UM patients [4].…”