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Serdar Yavuzyigitoglu, Wojtek Drabarek, Kyra N Smit, Askar Obulkasim, Natasha van Poppelen, Anna Koopmans, Jolanda Vaarwater, Tom Brands, Bert Eussen, Hendrikus J Dubbink, Robert Verdijk, Nicole Naus, Dion Paridaens, Emine Kilic, Annelies de Klein; Molecular classification of uveal melanoma subtypes using integrative mutational and whole-genome copy number analysis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2502. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Classification of structural and numerical chromosomal changes to elucidate the observed metastatic risk difference in uveal melanoma (UM) patients with mutually exclusive BAP1, SF3B1 and EIF1AX mutations.
Unsupervised hierarchical clustering of genome-wide single nucleotide polymorphism (SNP) array data was used to identify molecular subclasses with distinct chromosomal patterns. These subclasses were then investigated for mutations in BAP1, SF3B1 and EIF1AX by next-generation sequencing, Sanger sequencing and immunohistochemistry (IHC).
Unsupervised clustering identified five clusters with distinct copy number aberrations patterns, based on copy number variations (CNVs) of chromosome 3, chromosome 6 and chromosome 8. Chromosome 3 divided the cases in two major clusters, in which monosomy 3 UMs were enriched for BAP1 IHC negative UMs. BAP1 IHC positive UMs harboring BAP1 mutations also clusters along BAP1 negative UMs. Within the disomy 3 UMs, the three subclusters were based on chromosome 6 CNVs. UMs with disomy 6 and gain of entire chromosome 6 UMs were enriched for EIF1AX mutations, whereas partial chromosome 6p accompanied by partial chromosome 8q gain were SF3B1-mutated UMs.
UMs are characterized by recurrent CNVs and recurrent mutated genes. Unsupervised clustering revealed that UMs can be classified in distinct subclasses which are characterized by the same CNVs and recurrent mutated genes. UMs harboring mutations in BAP1, SF3B1 or EIF1AX have distinct chromosomal aberration patterns that mainly differ by the affected chromosomes, the absolute number of CNVs and the type of CNVs. Mutations in these genes are strongly associated with distinct molecular subclasses. This highlights and reflects the biological difference between UMs on a genetic level.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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