scholarly journals Spliceosome Mutations in Uveal Melanoma

2020 ◽  
Vol 21 (24) ◽  
pp. 9546
Author(s):  
Josephine Q.N. Nguyen ◽  
Wojtek Drabarek ◽  
Serdar Yavuzyigitoglu ◽  
Eva Medico Salsench ◽  
Robert M. Verdijk ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Late Onset ◽  
Metastatic Potential ◽  
Vital Role ◽  
Tumor Classification ◽  
Splicing Factor ◽  
Driver Genes ◽  
Distinct Subgroup ◽  
Recurrent Mutations

Uveal melanoma (UM) is the most common primary intraocular malignancy of the eye. It has a high metastatic potential and mainly spreads to the liver. Genetics play a vital role in tumor classification and prognostication of UM metastatic disease. One of the driver genes mutated in metastasized UM is subunit 1 of splicing factor 3b (SF3B1), a component of the spliceosome complex. Recurrent mutations in components of the spliceosome complex are observed in UM and other malignancies, suggesting an important role in tumorigenesis. SF3B1 is the most common mutated spliceosome gene and in UM it is associated with late-onset metastasis. This review summarizes the genetic and epigenetic insights of spliceosome mutations in UM. They form a distinct subgroup of UM and have similarities with other spliceosome mutated malignancies.

scholarly journals Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma

2013 ◽  
Vol 45 (2) ◽  
pp. 133-135 ◽  
Author(s):  
J William Harbour ◽  
Elisha D O Roberson ◽  
Hima Anbunathan ◽  
Michael D Onken ◽  
Lori A Worley ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Splicing Factor ◽  
Recurrent Mutations

scholarly journals Prognostic Value of the Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Uveal Melanoma: A Clinico-Pathological and Immunohistochemical Study on a Series of 85 Cases

2021 ◽  
Vol 11 (17) ◽  
pp. 7874
Author(s):  
Giuseppe Broggi ◽  
Luca Falzone ◽  
Matteo Fallico ◽  
Andrea Russo ◽  
Michele Reibaldi ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Rna Binding ◽  
Metastatic Potential ◽  
Splicing Factor ◽  
Survival Times ◽  
Immunohistochemical Expression ◽  
Free Survival ◽  
Metastatic Risk ◽  
Factor Α ◽  
Splicing Factor 1

Uveal melanoma (UM) is the most frequent primary ocular malignancy of adults; it exhibits an almost invariably poor prognosis with onset of liver metastases within 10–15 years after the diagnosis. Serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein with proto-oncogene functions, including stimulation of angiogenesis, cell migration and cell growth; regarding the complex regulation of tumor angiogenesis, it has been suggested that SRSF1 regulates the alternative splicing of vascular endothelial growth factor-α, promoting the formation of its pro-angiogenic isoform. The immunohistochemical expression of SRSF1 on a series of 85 primary UMs, including 39 metastasizing and 46 non-metastasizing cases, was investigated; to clarify the potential pathogenetic role of SRSF1 in this tumor and its effect on angiogenesis, we correlated our immunohistochemical findings with the clinico-pathological features, the prognostic data and blood vascular microvessel density (MVD) findings of the cases from our series. Cases with higher immunohistochemical expression of SRSF1 also had higher MVD, higher metastatic potential and shorter metastasis-free survival; conversely, cases with lower SRSF1 immunoexpression showed lower MVD, lower metastatic risk and longer metastasis-free survival times. Our results suggested that SRSF1 has a negative prognostic role and a pro-angiogenic function in UM.

Late-onset systemic lupus erythematosus in Latin Americans: a distinct subgroup?

Lupus ◽  
2014 ◽  
Vol 24 (8) ◽  
pp. 788-795 ◽  
Author(s):  
L J Catoggio ◽  
E R Soriano ◽  
P M Imamura ◽  
D Wojdyla ◽  
S Jacobelli ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Late Onset ◽  
Systemic Lupus ◽  
Latin Americans ◽  
Distinct Subgroup ◽  
Onset Systemic Lupus Erythematosus

scholarly journals Splicing factor gene mutations in hematologic malignancies

Blood ◽  
2017 ◽  
Vol 129 (10) ◽  
pp. 1260-1269 ◽  
Author(s):  
Borja Saez ◽  
Matthew J. Walter ◽  
Timothy A. Graubert
Keyword(s):  
Animal Models ◽  
Messenger Rna ◽  
Gene Mutations ◽  
Hematologic Malignancies ◽  
Splicing Factor ◽  
Hematopoietic Malignancy ◽  
Healthy Elderly ◽  
Increased Risk ◽  
Recurrent Mutations ◽  
Clinical Consequences

Abstract Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway.

scholarly journals Secondary Somatic Mutations in G-Protein-Related Pathways and Mutation Signatures in Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1688 ◽  
Author(s):  
Francesca Piaggio ◽  
Veronica Tozzo ◽  
Cinzia Bernardi ◽  
Michela Croce ◽  
Roberto Puzone ◽  
...  
Keyword(s):  
G Protein ◽  
Uveal Melanoma ◽  
Tumor Development ◽  
Splicing Factor ◽  
Driver Mutations ◽  
Driver Gene ◽  
Protein Subunit ◽  
Mutational Signatures ◽  
Kegg Pathways ◽  
Tyrosine Kinase 2

Background: Uveal melanoma (UM), a rare cancer of the eye, is characterized by initiating mutations in the genes G-protein subunit alpha Q (GNAQ), G-protein subunit alpha 11 (GNA11), cysteinyl leukotriene receptor 2 (CYSLTR2), and phospholipase C beta 4 (PLCB4) and by metastasis-promoting mutations in the genes splicing factor 3B1 (SF3B1), serine and arginine rich splicing factor 2 (SRSF2), and BRCA1-associated protein 1 (BAP1). Here, we tested the hypothesis that additional mutations, though occurring in only a few cases (“secondary drivers”), might influence tumor development. Methods: We analyzed all the 4125 mutations detected in exome sequencing datasets, comprising a total of 139 Ums, and tested the enrichment of secondary drivers in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that also contained the initiating mutations. We searched for additional mutations in the putative secondary driver gene protein tyrosine kinase 2 beta (PTK2B) and we developed new mutational signatures that explain the mutational pattern observed in UM. Results: Secondary drivers were significantly enriched in KEGG pathways that also contained GNAQ and GNA11, such as the calcium-signaling pathway. Many of the secondary drivers were known cancer driver genes and were strongly associated with metastasis and survival. We identified additional mutations in PTK2B. Sparse dictionary learning allowed for the identification of mutational signatures specific for UM. Conclusions: A considerable part of rare mutations that occur in addition to known driver mutations are likely to affect tumor development and progression.

scholarly journals Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

2011 ◽  
Vol 44 (1) ◽  
pp. 53-57 ◽  
Author(s):  
Timothy A Graubert ◽  
Dong Shen ◽  
Li Ding ◽  
Theresa Okeyo-Owuor ◽  
Cara L Lunn ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Splicing Factor ◽  
Recurrent Mutations

scholarly journals Data Fusion Techniques for the Integration of Multi-Domain Genomic Data from Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1434 ◽  
Author(s):  
Max Pfeffer ◽  
André Uschmajew ◽  
Adriana Amaro ◽  
Ulrich Pfeffer
Keyword(s):  
Gene Expression ◽  
Data Fusion ◽  
Uveal Melanoma ◽  
Copy Number ◽  
Somatic Mutations ◽  
Genomic Data ◽  
The Cancer Genome Atlas ◽  
Driver Genes ◽  
Discrimination Power ◽  
Value Decomposition

Uveal melanoma (UM) is a rare cancer that is well characterized at the molecular level. Two to four classes have been identified by the analyses of gene expression (mRNA, ncRNA), DNA copy number, DNA-methylation and somatic mutations yet no factual integration of these data has been reported. We therefore applied novel algorithms for data fusion, joint Singular Value Decomposition (jSVD) and joint Constrained Matrix Factorization (jCMF), as well as similarity network fusion (SNF), for the integration of gene expression, methylation and copy number data that we applied to the Cancer Genome Atlas (TCGA) UM dataset. Variant features that most strongly impact on definition of classes were extracted for biological interpretation of the classes. Data fusion allows for the identification of the two to four classes previously described. Not all of these classes are evident at all levels indicating that integrative analyses add to genomic discrimination power. The classes are also characterized by different frequencies of somatic mutations in putative driver genes (GNAQ, GNA11, SF3B1, BAP1). Innovative data fusion techniques confirm, as expected, the existence of two main types of uveal melanoma mainly characterized by copy number alterations. Subtypes were also confirmed but are somewhat less defined. Data fusion allows for real integration of multi-domain genomic data.

scholarly journals Immunoexpression of Macroh2a in Uveal Melanoma

2019 ◽  
Vol 9 (16) ◽  
pp. 3244 ◽  
Author(s):  
Salvatorelli ◽  
Puzzo ◽  
Bartoloni ◽  
Palmucci ◽  
Longo ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Cutaneous Melanoma ◽  
High Expression ◽  
Melanoma Metastasis ◽  
Proper Treatment ◽  
Immunohistochemical Expression ◽  
Prognostic Role

MacroH2A is a histone variant whose expression has been studied in several neoplasms, including cutaneous melanomas (CMs). In the literature, it has been demonstrated that macroH2A.1 levels gradually decrease during CM progression, and a high expression of macroH2A.1 in CM cells relates to a better prognosis. Although both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma (UM) is biologically and genetically distinct from the more common cutaneous melanoma. Metastasis to the liver is a frequent occurrence in UM, and about 40%–50% of patients die of metastatic disease, even with early diagnosis, proper treatment, and close follow-up. We wanted to investigate macroH2A.1 immunohistochemical expression in UM. Our results demonstrated that mH2A.1 expression was higher in metastatic UM (21/23, 91.4%), while only 18/32 (56.3%). UMs without metastases showed mH2A.1 staining. These data could suggest a possible prognostic role for mH2A.1 and could form a basis for developing new pharmacological strategies for UM treatment.

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