van Poppelen Natasha M, Drabarek Wojtek, Smit Kyra N, Vaarwater Jolanda, Brands Tom, Paridaens Dion, Kiliç Emine, de Klein Annelies
Department of Ophthalmology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
Cancers (Basel). 2019 Aug 17;11(8):1200. doi: 10.3390/cancers11081200.
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.
葡萄膜黑色素瘤（UM）是西方世界成年人中最常见的原发性眼部恶性肿瘤。具有剪接体基因 突变的UM的特征是染色体1、6、8、9或11发生三个或更多结构变化。此外，没有 突变的UM也存在类似的染色体畸变。由于除了 之外，在血液系统恶性肿瘤中也观察到 和 的突变，因此没有 突变但具有特征性染色体模式的UM可能在这些基因之一中存在突变。根据染色体图谱和野生型 状态选择了42例UM。对从肿瘤组织中提取的DNA进行了覆盖 （外显子2和7）热点和 （外显子1和2）的桑格测序。从癌症基因组图谱（TCGA）中提取了三个具有 突变的UM的数据。在42个选定肿瘤中的两个UM（5%）和三个TCGA UM标本中检测到影响氨基酸92 - 100的杂合框内 缺失。我们队列中具有 突变的UM和TCGA的UM样本均显示出四个以上的染色体结构畸变，包括（部分）6号和8号染色体的增加，尽管在两个TCGA UM中观察到3号染色体单体性。虽然在骨髓增生异常综合征中主要描述的是错义 突变，但在UM中观察到的 突变均为8 - 9个氨基酸的框内缺失。这表明UM中的R625错义SF3B1突变和SRSF2突变与血液系统癌症中的剪接体基因突变不同，并且可能靶向参与葡萄膜黑色素瘤病因的一组不同的、尚未知的基因。
