Mutations in Uveal Melanoma: A Preference for In-Frame Deletions?

Uveal melanoma (UM) is the most common primary ocular malignancy in adults in the Western world. UM with a mutation in , a spliceosome gene, is characterized by three or more structural changes of chromosome 1, 6, 8, 9, or 11. Also UM without a mutation in harbors similar chromosomal aberrations. Since, in addition to , mutations in and have also been observed in hematological malignancies, UM without a mutation-but with the characteristic chromosomal pattern-might harbor mutations in one of these genes. 42 UMs were selected based on their chromosomal profile and wildtype status. Sanger sequencing covering the (exon 2 and 7) hotspots and (exon 1 and 2) was performed on DNA extracted from tumor tissue. Data of three UM with an mutation was extracted from the The Cancer Genome Atlas (TCGA). Heterozygous in-frame deletions affecting amino acids 92-100 were detected in two UMs (5%) of 42 selected tumors and in three TGCA UM specimens. Both the UM with an mutation from our cohort and the UM samples from the TCGA showed more than four structural chromosomal aberrations including (partial) gain of chromosome 6 and 8, although in two TCGA UMs monosomy 3 was observed. Whereas in myelodysplastic syndrome predominantly missense mutations are described, the observed mutations in UM are all in-frame deletions of 8-9 amino acids. This suggests that the R625 missense SF3B1 mutations and SRSF2 mutations in UM are different compared to the spliceosome gene mutations in hematological cancers, and probably target a different, as yet unknown, set of genes involved in uveal melanoma etiology.