Systematic Profiling of Alternative Splicing Events in Ovarian Cancer

Liu, Jia; Lv, Dekang; Wang, Xiaobin; Wang, Ruicong; Li, Xiaodong

doi:10.3389/fonc.2021.622805

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…The AS events of OC patients was downloaded from the TCGA Spliceseq database (https://bioinformatics.mdanderson.org/TCGASpliceSeq/PSIdownload.jsp), and the splicing percentage (PSI) is obtained. AS events with PSI≥75% were included in this study (Liu et al, 2021…”

Section: Data Acquisitionmentioning

confidence: 99%

Identification of a Potential Alternative Splicing Prognostic Signature Associated With Immune Infiltrates of Ovarian Cancer

Han

Wang

2021

Preprint

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Background: The mortality rate of ovarian cancer (OC) ranks the first in gynecological tumors, which seriously threatens women's health and life. In recent years, alternative splicing (AS) has gradually been considered to play a key role in immune infiltrates of tumor. However, the prognostic significance of AS events related to immune infiltrates in OC remains unknow. The aim of our research was to investigate the potential prognostic value of AS events associated with immune infiltrates in OC.Methods: The RNA sequences (RNA-seq) and clinical data were downloaded from the Cancer Genome Atlas (TCGA) database. The AS event data was obtained from TCGA SpliceSeq database. Single sample gene set enrichment analysis (ssGSEA) was performed to calculate the abundance of 28 immune cell types in samples from TCGA-OV dataset. A consensus clustering algorithm was used to group the OC patients. Differential expression analysis was used to identify differentially expressed AS events (DEASs) between groups. Univariate Cox regression analysis was implemented to screen for AS events with prognostic value. A least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression analyses was used to further narrow the AS events with prognostic value and construct an alternative splicing prognostic signature for predicting the prognosis of OC patients. Results: The OC patients from TCGA database were classified into two groups (cluster.A and cluster.B) based on the 28 types of TIIC using a consensus clustering algorithm. The patients in the cluster.A group had increased immune infiltrates compared with the cluster.B group. 3616 DEASs were acquired and 171 DEASs have prognostic value (p<0.05). 28 DEASs with prognostic value (p<0.001) were fitted into LASSO Cox regression and multivariate Cox regression analyses. A prognostic signature with 18 DEASs was constructed to predict the prognosis of OC patients. Each patient obtained a riskscore and the patients were classified into high-and low-risk group using the median riskscore as a cutoff. Kaplan-Meier curve revealed that the patients in high-risk group have poor outcome. Conclusions: Collectively, our research identified an alternative splicing prognostic signature associated with immune infiltrates of OC, which may provide new directions for the immunotherapy of OC patients.

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Section: Data Acquisitionmentioning

confidence: 99%

Identification of a Potential Alternative Splicing Prognostic Signature Associated With Immune Infiltrates of Ovarian Cancer

Han

Wang

2021

Preprint

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“…However, dysregulated alternative splicing can promote tumorigenesis and chemoresistance (18)(19)(20)(21)(22). In ovarian cancer, splicing factors are frequently upregulated (23), and several subsets of alternative splicing events have been associated with disease progression and patient prognosis (24)(25)(26)(27)(28)(29)(30). Many DNA repair genes are regulated by alternative splicing and targeting spliceosome components have been shown to sensitize cancer cells to PARP inhibitors by disrupting the expression of genes such as ATM, RAD51 and CHEK1 (31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Spear

et al. 2023

Preprint

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Ovarian high-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer with limited therapeutic options. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Therapies disrupting the spliceosome alter cancer transcriptomes and have shown potential to improve PARP inhibitor response. Indisulam (E7070) has been identified as a molecular glue that brings splicing factor RBM39 and DCAF15 E3 ubiquitin ligase in close proximity. Exposure to indisulam induces RBM39 proteasomal degradation through DCAF15-mediated polyubiquitination and subsequent RNA splicing defects. In this study, we demonstrate that loss of RBM39 induces splicing errors in DNA damage repair genes in ovarian cancer, leading to increased sensitivity to PARP inhibitors such as olaparib. Indisulam synergized with olaparib in multiple in vitro models of ovarian cancer regardless of PARP inhibitor sensitivity and improved olaparib response in mice bearing PARP inhibitor-resistant tumors. DCAF15 expression, but not BRCA1/2 mutational status, was essential for the synergy between indisulam and olaparib, suggesting that the combination therapy may benefit patients irrespective of their BRCA1/2 status. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improving PARP inhibitor response in ovarian HGSC.

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“…Also, splice factors UBAP2L, which regulates the expression of TRA2B, and RPS24 of SYNCRIP are associated with poor survival ( Sun and Yang, 2020 ). Hence studying alternative splice forms and splicing factors aberrations can be beneficial as targets for therapeutic interventions ( Liu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Multi-omics analysis of the Indian ovarian cancer cohort revealed histotype-specific mutation and gene expression patterns

et al. 2023

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Introduction: In India, OVCa is women’s third most common and lethal cancer type, accounting for 6.7% of observed cancer incidences. The contribution of somatic mutations, aberrant expression of gene and splice forms in determining the cell fate, gene networks, tumour-specific variants, and the role of immune fraction infiltration have been proven essential in understanding tumorigenesis. However, their interplay in OVCa in a histotype-specific manner remains unclear in the Indian context. In the present study, we aimed to unravel the Indian population histotype-specific exome variants, differentially expressed gene modules, splice events and immune profiles of OVCa samples.Methods: We analysed 10 tumour samples across 4 ovarian cancer histotypes along with 2 normal patient samples. This included BCFtool utilities and CNVkit for exome, WGCNA and DESeq2 for obtaining differential module hub genes and dysregulated miRNA targets, CIBERSORTx for individual immune profiles and rMATS for tumour specific splice variants.Result: We identified population-specific novel mutations in Cancer Gene Census Tier1 and Tier2 genes. MUC16, MUC4, CIITA, and NCOR2 were among the most mutated genes, along with TP53. Transcriptome analysis showed significant overexpression of mutated genes MUC16, MUC4, and CIITA, whereas NCOR2 was downregulated. WGCNA revealed histotype-specific gene hubs and networks. Among the significant pathways, alteration in the immune system was one of the pathways, and immune profiling using CIBERSORTx revealed histotype-specific immune cell fraction. miRNA analysis revealed miR-200 family, miR-200a and miR-429 were upregulated in HGSOCs.Splice factor abrasion caused splicing perturbations, with the most abundant alternative splice event being exon skipping and the most spliced gene, SNHG17. Pathway analysis of spliced genes revealed translational elongation and Base excision repair as the pathways altered in OVCa.Conclusion: Integrated exome, transcriptome, and splicing patterns revealed different population-specific molecular signatures of ovarian cancer histotypes in the Indian Cohort.

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Systematic Profiling of Alternative Splicing Events in Ovarian Cancer

Cited by 3 publications

References 35 publications

Identification of a Potential Alternative Splicing Prognostic Signature Associated With Immune Infiltrates of Ovarian Cancer

Identification of a Potential Alternative Splicing Prognostic Signature Associated With Immune Infiltrates of Ovarian Cancer

Pharmacological depletion of RNA splicing factor RBM39 by indisulam synergizes with PARP inhibitors in high-grade serous ovarian carcinoma

Multi-omics analysis of the Indian ovarian cancer cohort revealed histotype-specific mutation and gene expression patterns

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