Recurrent Spliceosome Mutations in Cancer: Mechanisms and Consequences of Aberrant Splice Site Selection

Niño, Carlos A Martínez; Perrotolo, Rossella Scotto di; Polo, Simona

doi:10.3390/cancers14020281

Cited by 5 publications

(6 citation statements)

References 66 publications

(172 reference statements)

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“…Among them, spliceosome in uences cancer up to an extent. Research has shown that certain components of spliceosomes, including U1 snRNA, SF3B1, and U2AF1, may be related to tumors, which are critically involved in cancer progression [20,21]. A study indicates that chronic cerebral hypoperfusion (CCH) can simultaneously trigger the coagulation and complement cascade in a new Alzheimer's disease mouse model brain, potentially expediting AD pathology.…”

Section: Discussionmentioning

confidence: 99%

Identification of lipid metabolism-related genes and their roles in Alzheimer’s disease: a multi-omics analysis

Liu

Long

et al. 2023

Preprint

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Background: Alzheimer's disease (AD) is a neurological condition that worsens with time. It is distinguished by the buildup of improperly folded amyloid beta protein, which produces amyloid plaques and promotes tau protein aggregation into neurofibrillary tangles in the brain. Certain lipids are critically involved in the development of AD, for instance, apolipoprotein E (ApoE), which is involved in lipid metabolism and cholesterol metabolism in the body and functions as a genetic risk factor for AD. However, there is currently a lack of systematic understanding of how Lipid Metabolism-related Genes (LMGs) contribute to AD. This study aimed to identify potential biomarkers for early AD diagnosis to address this knowledge gap, specifically focusing on those associated with immune cell infiltration. Machine-learning algorithms and Gene Expression Omnibus (GEO) database were utilized to achieve this goal. Methods: Differentially expressed genes (DEGs) between healthy and AD patient samples were identified. The process involved using two expression profiles retrieved from the Gene Expression Omnibus（GEO）database, including the publicly available GSE5281 and GSE138260. Furthermore, functional enrichment analysis was conducted. The samples were randomly classified to either the training or the validation sets to ensure reliable results. This involved assessing Lipid Metabolism-related DEGs (LMDEGs) between AD and healthy tissues. To identify the potential gene biomarker, the machine-learning algorithm Support Vector Machine-Recursive Feature Elimination (SVM-RFE) and the Least Absolute Shrinkage and Selection Operator (LASSO) regression model were applied.The algorithm called cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was utilized to assess the role of infiltrating immune cells and their association with the gene biomarker. Finally, the Integrated Traditional Chinese Medicine (ITCM) database was utilized to identify associated Chinese medicines and evaluate the association of related herbal medicines with lipid metabolism and AD. Results: A total of 137 genes were extracted from 751 LMGs that depicted a strong correlation with autophagy regulation and immune response. LASSO and SVM-RFE were employed to determine choline acetyl transferase (CHAT), member RAS oncogene family (RAB4A), acyl-coA binding domain-containing protein 6 (ACBD6), and alpha-galactosidase A (GLA) as marker genes among the 137 AD-related genes. These genes exhibited promising treatment capabilities.Functional enrichment analysis was conducted to explore their involvement in various processes. The data indicated a link between these genes and the cell cycle, amino acid metabolism, immune response regulation, and various processes associated with AD pathogenesis.Moreover, nine Chinese Medicine drugs were identified that specifically target the four marker genes. Furthermore, the ceRNA network revealed an intricate regulatory correlation involving these marker genes. Additionally, CIBERSORT analysis implied that alterations in the immune microenvironment of individuals with AD may be associated with CHAT. Conclusion: These findings hold significant diagnostic potential and provide insights into the mechanism of AD. Nonetheless, additional research is essential to assess the diagnostic value of these markers for clinical application. This research sheds light on the involvement of LMGs in the mechanism involved in AD pathogenesis. The acquired data aid the treatment of the disease by providing potential therapeutic targets. This research contributes to a better comprehension of the disease and its underlying processes. Furthermore, it facilitates further research by providing a foundation for developing more effective strategies for diagnostic and therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

Identification of lipid metabolism-related genes and their roles in Alzheimer’s disease: a multi-omics analysis

Liu

Long

et al. 2023

Preprint

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“…These findings implied that the WDR4 rs6586250 T allele could regulate the expression of multiple surrounding genes. RNA splicing is essential for generating mature messenger RNA (mRNA) and regulating gene expression, thereby affecting cellular processes and cell fates, and is catalyzed by a ribonucleoprotein complex called the spliceosome 47 . U2AF1, the subunit of the U2 auxiliary factor (U2AF) heterodimer and an indispensable component of the spliceosome, has the ability to specifically recognize the AG dinucleotide of the 3' splice sites and promote the process of RNA splicing.…”

Section: Discussionmentioning

confidence: 99%

“…U2AF1, the subunit of the U2 auxiliary factor (U2AF) heterodimer and an indispensable component of the spliceosome, has the ability to specifically recognize the AG dinucleotide of the 3' splice sites and promote the process of RNA splicing. Furthermore, mutations in U2AF1 were associated with hematological malignancies and myelodysplasia syndromes 47 . According to our analysis, a low expression level of U2AF1 might affect the activity or efficiency of RNA splicing, leading to the possibility of tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

WDR4 gene polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study

Deng¹,

Hua²,

Deng³

et al. 2023

J. Cancer

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Wilms tumor is the most common embryonal renal malignancy in children. WDR4 is an indispensable noncatalytic subunit of the RNA N7-methylguanosine (m7G) methyltransferase complex and plays an essential role in tumorigenesis. However, the relationship between polymorphisms in the WDR4 gene and susceptibility to Wilms tumor remains to be fully investigated. We performed a large case-control study involving 414 patients and 1199 cancer-free controls to investigate whether single nucleotide polymorphisms (SNPs) in the WDR4 gene are associated with Wilms tumor susceptibility. WDR4 gene polymorphisms (rs2156315 C > T, rs2156316 C > G, rs6586250 C > T, rs15736 G > A, and rs2248490 C > G) were genotyped using the TaqMan assay. In addition, unconditioned logistic regression analysis was performed, odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the association between WDR4 gene SNPs and Wilms tumor susceptibility as well as the strength of the associations. We found that only the rs6586250 C>T polymorphism was significantly associated with an increased risk of Wilms tumor (adjusted OR=2.99, 95% CI = 1.28-6.97, P = 0.011 for the rs6586250 TT genotype; adjusted OR=3.08, 95% CI = 1.33-7.17, P = 0.009 for the rs6586250 CC/CT genotype). Furthermore, the stratification analysis revealed that patients with the rs6586250 TT genotype and carriers with 1-5 risk genotypes exhibited statistically significant associations with increased Wilms tumor risk in specific subgroups. However, the rs2156315 CT/TT genotype was identified as having a protective effect against Wilms tumor in the age >18 months subgroup compared with the rs2156315 CC genotype. In brief, our study demonstrated that the rs6586250 C > T polymorphism of the WDR4 gene was significantly associated with Wilms tumor. This finding may contribute to the understanding of the genetic mechanism of Wilms tumor.

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“…Moreover, mutations in other proteins and non-coding RNAs in splicing regulation with lower frequency have been shown to play important roles in myeloid neoplasms, too. Mutations in genes encoding the U1 and U11 snRNAs responsible for recognition of the 5′ss in the major and minor spliceosomes were found in CLL and other cancer types [ 62 , 63 ]. Factors in the hnRNP family function to repress splicing as opposed to SR proteins [ 21 ], and mutations in HNRNPH1 are found to be associated with adverse outcomes in mantle cell lymphoma [ 64 ].…”

Section: The Discovery and Pathogenic Roles Of Splicing Factor Mutati...mentioning

confidence: 99%

Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations

Zhang

Chen

2022

Biomedicines

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Splicing factors are frequently mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations are presumed to contribute to oncogenic transformation, but the underlying mechanisms remain incompletely understood. While no specific treatment option is available for MDS/AML patients with spliceosome mutations, novel targeting strategies are actively explored, leading to clinical trials of small molecule inhibitors that target the spliceosome, DNA damage response pathway, and immune response pathway. Here, we review recent progress in mechanistic understanding of splicing factor mutations promoting disease progression and summarize potential therapeutic strategies, which, if successful, would provide clinical benefit to patients carrying splicing factor mutations.

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Recurrent Spliceosome Mutations in Cancer: Mechanisms and Consequences of Aberrant Splice Site Selection

Cited by 5 publications

References 66 publications

Identification of lipid metabolism-related genes and their roles in Alzheimer’s disease: a multi-omics analysis

Identification of lipid metabolism-related genes and their roles in Alzheimer’s disease: a multi-omics analysis

WDR4 gene polymorphisms and Wilms tumor susceptibility in Chinese children: A five-center case-control study

Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations

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