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SRSF2 Mutations in Uveal Melanoma: A Preference for In-Frame Deletions?

Cancers (Basel) 2019, vol. 11, issue 8

Background:

Uveal melanoma (UM) is the most common primary ocular malignancy in adults in the Western world. UM with a mutation in

SF3B1

, 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

SF3B1

harbors similar chromosomal aberrations. Since, in addition to

SF3B1

, mutations in

U2AF1

and

SRSF2

have also been observed in hematological malignancies, UM without a

SF3B1

mutation-but with the characteristic chromosomal pattern-might harbor mutations in one of these genes.

Methods:

42 UMs were selected based on their chromosomal profile and wildtype

SF3B1

status. Sanger sequencing covering the

U2AF1

(exon 2 and 7) hotspots and

SRSF2

(exon 1 and 2) was performed on DNA extracted from tumor tissue. Data of three UM with an

SRSF2

mutation was extracted from the The Cancer Genome Atlas (TCGA).

Results:

Heterozygous in-frame

SRSF2

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

SRSF2

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.

Conclusions:

Whereas in myelodysplastic syndrome predominantly missense

SRSF2

mutations are described, the observed

SRSF2

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.

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