Spliceosome Mutations in Uveal Melanoma

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies.

Keywords: DNA repair; chromosomes; epigenetic; genetic; metastatic disease; mutational analysis; prognosis; therapy.

Figure 1

Disease-specific survival plot of Uveal melanoma (UM) patients, defined as the first date of treatment until the date of metastasis or until last follow-up. Patients were censored when they were lost to follow-up or when death from a cause other than UM occurred. Updated Kaplan-Meier curve of SF3B1-mutated UM adapted and updated from Yavuzyigitoglu et al. [21]. Three groups of patients with secondary driver gene mutations: n = 185; EIF1AX, n = 33; SF3B1, n = 63; BAP1, n = 89).

Figure 2

Splicing of pre-mRNA into mature mRNA. (a) Overview of different complexes in the spliceosome. (b) Splicing in wild-type SF3B1 (SF3B1^WT) cells: SF3B1^WT binds to the branchpoint of the pre-mRNA, usually an adenosine. When this process is executed correctly, mature mRNA is formed which results in a canonical protein. (c) Splicing in mutated SF3B1 (SF3B1^MUT) cells: SF3B1^MUT recognizes an alternative branchpoint, which leads to mis-splicing of the mRNA (e.g., intron retention, exon skipping and intronic extension of exon). The mis-spliced mRNA can be translated into aberrant proteins or be degraded by nonsense-mediated decay (NMD), resulting in downregulation of gene expression.

Figure 3

Overview of SF3B1 mutations in UM, hematological cancers, breast cancer and mucosal melanoma. Squares represent singleton mutations. Dots represent mutations seen at least two times. Underline represents hotspot mutations. Singleton mutations are only displayed for the UM cohort. For the hematological cancers and breast cancer cohorts only mutations with frequency of ≥5% are reported (see supplementary Table S1 for other data (Catalogue of Somatic Mutations in cancer v92, 27-08-2020, [46]).

Figure 4

Three-dimensional view of the proteins. (a) SF3B1 protein with hotspot residue R625, K666 and K700. (b) SRSF2 protein with hotspot P95.

Figure 5

Example of the complex chromosome aberrations of a SF3B1-mutated tumour of a 38 year old female. Shown is (a) metaphase spread with DAPI staining, (b) spectral karyotyping in which each chromosome has a specific color, (c) red chromosome 8 paint and green telomeric 6q probe and (d) spectral karyotype showing exchanges between different chromosomes. For instance, part of chr6 (red) is attached to the bottom part (q-arm) of chromosome 5 (orange). The upper arm (p-arm) of chromosome 7 has material of chromosome 11 (blue) and 8 (green). Full karyotype in Naus et al. [53].