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

Poppelen, Natasha M. van; Drabarek, Wojtek; Smit, Kyra N.; Vaarwater, Jolanda; Brands, Tom; Paridaens, Dion; Kılıç, Emine; Klein, Annelies de

doi:10.3390/cancers11081200

Cited by 23 publications

(24 citation statements)

References 17 publications

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“…Due to their low frequency in this study, no association could be made between the mutations in TTC28, CSMD1, KTN1 or TP53BP1 and UM with particular clinical or morphological features. It is worth noting that previously described mutations in SRSF2, DLK2 or FBXW7 were not detected in this large study [14,20,45].…”

Section: Other Mutationscontrasting

confidence: 47%

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

Thornton

Coupland

Olohan

et al. 2020

Cancers

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Uveal melanoma (UM) has well-characterised somatic copy number alterations (SCNA) in chromosomes 1, 3, 6 and 8, in addition to mutations in GNAQ, GNA11, CYSLTR2, PLCB4, BAP1, SF3B1 and EIF1AX, most being linked to metastatic-risk. To gain further insight into the molecular landscape of UM, we designed a targeted next-generation sequencing (NGS) panel to detect SCNA and mutations in routine clinical UM samples. We compared hybrid-capture and amplicon-based target enrichment methods and tested a larger cohort of primary UM samples on the best performing panel. UM clinical samples processed either as fresh-frozen, formalin-fixed paraffin embedded (FFPE), small intraocular biopsies or following irradiation were successfully profiled using NGS, with hybrid capture outperforming the PCR-based enrichment methodology. We identified monosomy 3 (M3)-UM that were wild-type for BAP1 but harbored SF3B1 mutations, novel frameshift deletions in SF3B1 and EIF1AX, as well as a PLCB4 mutation outside of the hotspot on exon 20 coinciding with a GNAQ mutation in some UM. We observed samples that harboured mutations in both BAP1 and SF3B1, and SF3B1 and EIF1AX, respectively. Novel mutations were also identified in TTC28, KTN1, CSMD1 and TP53BP1. NGS can simultaneously assess SCNA and mutation data in UM, in a reliable and reproducible way, irrespective of sample type or previous processing. BAP1 and SF3B1 mutations, in addition to 8q copy number, are of added importance when determining UM patient outcome.

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Section: Other Mutationscontrasting

confidence: 47%

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

Thornton

Coupland

Olohan

et al. 2020

Cancers

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“… 91 , 92 Heterozygous in-frame deletions in another spliceosome factor, SRSF2 , have been detected in 5% of UM cases, affecting amino acid residues 92–100. 93 Recently, mutations in EIF1AX (p.N4S), located in the X chromosome, have been detected in 13% of UM patients. 94 EIF1AX encodes a eukaryotic translation initiation factor 1A (eIF1A) that regulates the translation initiation process.…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Uveal melanoma: progress in molecular biology and therapeutics

Shi

Yang

et al. 2020

Ther Adv Med Oncol

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Uveal melanoma (UM) is the most common intraocular malignancy in adults. So far, no systemic therapy or standard treatment exists to reduce the risk of metastasis and improve overall survival of patients. With the increased knowledge regarding the molecular pathways that underlie the oncogenesis of UM, it is expected that novel therapeutic approaches will be available to conquer this disease. This review provides a summary of the current knowledge of, and progress made in understanding, the pathogenesis, genetic mutations, epigenetics, and immunology of UM. With the advent of the omics era, multi-dimensional big data are publicly available, providing an innovation platform to develop effective targeted and personalized therapeutics for UM patients. Indeed, recently, a great number of therapies have been reported specifically for UM caused by oncogenic mutations, as well as other etiologies. In this review, special attention is directed to advancements in targeted therapies. In particular, we discuss the possibilities of targeting: GNAQ/GNA11, PLCβ, and CYSLTR2 mutants; regulators of G-protein signaling; the secondary messenger adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6); downstream pathways, such as those involving mitogen-activated protein kinase/MEK/extracellular signal-related kinase, protein kinase C (PKC), phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR), Trio/Rho/Rac/Yes-associated protein, and inactivated BAP1; and immune-checkpoint proteins cytotoxic T-lymphocyte antigen 4 and programmed cell-death protein 1/programmed cell-death ligand 1. Furthermore, we conducted a survey of completed and ongoing clinical trials applying targeted and immune therapies for UM. Although drug combination therapy based on the signaling pathways involved in UM has made great progress, targeted therapy is still an unmet medical need.

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“…Deletions in spliceosome factors RBM10 , in-frame deletions of SRSF2 and homozygous deletion SF3A1 were found in only a few tumors [ 69 ]. Mutations in SRSF2 were all heterozygous in-frame deletions and starting at residue 92 or 03, except for one case described in The Cancer Genome Atlas (TCGA) starting at 174 [ 70 ].…”

Section: Genetics Of Ocular Melanomamentioning

confidence: 99%

Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing

Poppelen

Bruyn

Biçer

et al. 2020

IJMS

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Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. These malignancies derive from melanocytes in the uveal tract or conjunctiva. The genetic profiles of these different entities differ from each other. In uveal melanoma, GNAQ and GNA11 gene mutations are frequently found and prognosis is based on mutation status of BAP1, SF3B1 and EIF1AX genes. Iris melanoma, also originating from the uvea, has similarities to the genetic makeups of both posterior uveal melanoma (UM) and conjunctival melanoma since mutations in GNAQ and GNA11 are less common and genes involved in conjunctival melanoma such as BRAF have been described. The genetic spectrum of conjunctival melanoma, however, includes frequent mutations in the BRAF, NRAS and TERT promoter genes, which are found in cutaneous melanoma as well. The BRAF status of the tumor is not correlated to prognosis, whereas the TERT promoter gene mutations are. Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment.

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

Cited by 23 publications

References 17 publications

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

Targeted Next-Generation Sequencing of 117 Routine Clinical Samples Provides Further Insights into the Molecular Landscape of Uveal Melanoma

Uveal melanoma: progress in molecular biology and therapeutics

Genetics of Ocular Melanoma: Insights into Genetics, Inheritance and Testing

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