Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

Lin, Zijing; Gong, Jie; Zhong, Guo‐Chao; Hu, Jie‐Jun; Cai, Dong; Zhao, Lei; Zhang, Zhibo

doi:10.3389/fonc.2021.666847

Cited by 5 publications

(6 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among these, most reports focus on the relationship between aberrant ASEs and prognosis and survival in cancer patients. After identification of the overall survival-associated ASEs, prognostic models were developed to predict the survival outcomes of patients with aberrant AS patterns in gastric cancer ( 32 – 35 ), breast cancer ( 36 ), CHOL ( 37 ), glioblastoma ( 38 ), pancreatic cancer ( 39 ), LAML ( 40 ), UVM ( 41 ), HNSC ( 42 ), etc. Aberrant AS is also related to chemotherapy resistance.…”

Section: Discussionmentioning

confidence: 99%

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors

Duan,

Zhang,

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

BackgroundAlternative splicing events (ASEs) are vital causes of tumor heterogeneity in genitourinary tumors and many other cancers. However, the clinicopathological relevance of ASEs in cancers has not yet been comprehensively characterized.MethodsBy analyzing splicing data from the TCGA SpliceSeq database and phenotype data for all TCGA samples from the UCSC Xena database, we identified differential clinical feature-related ASEs in 33 tumors. CIBERSORT immune cell infiltration data from the TIMER2.0 database were used for differential clinical feature-related immune cell infiltration analysis. Gene function enrichment analysis was used to analyze the gene function of ASEs related to different clinical features in tumors. To reveal the regulatory mechanisms of ASEs, we integrated race-related ASEs and splicing quantitative trait loci (sQTLs) data in kidney renal clear cell carcinoma (KIRC) to comprehensively assess the impact of SNPs on ASEs. In addition, we predicted regulatory RNA binding proteins in bladder urothelial carcinoma (BLCA) based on the enrichment of motifs around alternative exons for ASEs.ResultsAlternative splicing differences were systematically analyzed between different groups of 58 clinical features in 33 cancers, and 30 clinical features in 24 cancer types were identified to be associated with more than 50 ASEs individually. The types of immune cell infiltration were found to be significantly different between subgroups of primary diagnosis and disease type. After integrating ASEs with sQTLs data, we found that 63 (58.9%) of the race-related ASEs were significantly SNP-correlated ASEs in KIRC. Gene function enrichment analyses showed that metastasis-related ASEs in KIRC mainly enriched Rho GTPase signaling pathways. Among those ASEs associated with metastasis, alternative splicing of GIT2 and TUBB3 might play key roles in tumor metastasis in KIRC patients. Finally, we identified several RNA binding proteins such as PCBP2, SNRNP70, and HuR, which might contribute to splicing differences between different groups of neoplasm grade in BLCA.ConclusionWe demonstrated the significant clinical relevance of ASEs in multiple cancer types. Furthermore, we identified and validated alternative splicing of TUBB3 and RNA binding proteins such as PCBP2 as critical regulators in the progression of urogenital cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors

Duan,

Zhang,

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Several prognostic models have been established in CCA based on signatures of mRNA, DNA methylation or alternative splicing ( 66 – 68 ). These prognostic models could help predict overall or disease-free survival and are beneficial to the individual management of CCA patients.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Estrogen Response Helps to Predict Prognosis and Identify Potential Therapeutic Targets in Cholangiocarcinoma

Miao

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways.

show abstract

Section: Altered Splicing Of Genes Involved In Liver Carcinogenesis and Metastasismentioning

confidence: 99%

“…Recently, a prognosis signature of genomic instability-related AS events has been identified for CCA data available at TCGA, without discriminating the anatomical location of the tumor [ 7 ]. Moreover, this signature could be associated with the presence of infiltrating immune cells and the expression of PD-L1 [ 7 ], having, therefore therapeutic impact. Thus, skipping exons 3 and 4 in FOXP3 mRNA leads to a frameshift in the open reading frame (ORF) and hence in the amino acid sequence of FOXP3 results in a different protein involved in the development of CD25+ regulatory T cells [ 138 ].…”

Section: Altered Splicing Of Genes Involved In Liver Carcinogenesis and Metastasismentioning

confidence: 99%

“…Because aberrant splicing generates mRNA isoforms involved in liver cancer development and malignancy [ 1 ], several studies have attempted to establish a relationship between alternative splicing (AS) signatures and the prognosis of HCC [ 2 , 3 , 4 , 5 ] and iCCA [ 6 , 7 ]. Editing immature mRNA (pre-mRNA) by splicing is carried out by the spliceosome, a multi-megadalton ribonucleoprotein complex in charge of introns removal and exons ligation as part of an integrated mechanism involved in gene regulatory network [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Impact of Alternative Splicing Variants on Liver Cancer Biology

Marin

Reviejo

Soto

et al. 2021

Cancers

View full text Add to dashboard Cite

The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

show abstract

Identification of Mutator-Derived Alternative Splicing Signatures of Genomic Instability for Improving the Clinical Outcome of Cholangiocarcinoma

Cited by 5 publications

References 35 publications

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors

Identification of alternative splicing associated with clinical features: from pan-cancers to genitourinary tumors

Characterization of the Estrogen Response Helps to Predict Prognosis and Identify Potential Therapeutic Targets in Cholangiocarcinoma

Impact of Alternative Splicing Variants on Liver Cancer Biology

Contact Info

Product

Resources

About