Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma

Kelley, Dylan Z.; Flam, Emily; Guo, Theresa; Danilova, Ludmila; Zamuner, Fernando T.; Bohrson, Craig L.; Considine, Michael; Windsor, Eric; Bishop, Justin A.; Zhang, Chi; Koch, Wayne M.; Sidransky, David; Westra, William H.; Chung, Christine H.; Califano, Joseph A.; Wheelan, Sarah J.; Favorov, Alexander V.; Florea, Liliana; Fertig, Elana J.; Gaykalova, Daria A.

doi:10.1016/j.trsl.2018.07.007

Cited by 11 publications

(8 citation statements)

References 42 publications

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“…According to our results, the CASEs were significantly enriched in GO categories and KEGG pathways that were closely related to HNSC initiation or maintenance. More importantly, two AS events recently validated as functional in HNSC were also identified in our study 61, 63, which further confirms the suitability of RNA-Seq as a method to investigate AS changes in cancer. We also evaluated the 473 CASEs in an independent cohort.…”

Section: Discussionsupporting

confidence: 85%

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Zheng

Wei

et al. 2019

Theranostics

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Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

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Section: Discussionsupporting

confidence: 85%

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Zheng

Wei

et al. 2019

Theranostics

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“…In the occurrence and development of HNSCC, epigenetic events play an important role, including DNA methylation, post-translational covalent modification of histones, chromatin remodeling and the effects of non-coding RNA (11)(12)(13)(14). Currently, an increasing number of splicing patterns have been found, such as the splicing variants of laminin subunit α3 (LAMA3), dystonin (DST), dedicator of cytokinesis (DOCK5), lysyl oxidase-like 2 (LOXL2) and gelsolin (GSN), and some studies have shown that these splicing variants can be used as cancer markers and potential therapeutic targets (15)(16)(17)(18). Some of these variants could even become novel antigens for specific targeted therapy of HNSCC, such as the splicing variant of GSN, which was reported to be able to serve as a biomarker of HNSCC and a neoantigen for HNSCC treatment (18).…”

Section: Introductionmentioning

confidence: 99%

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

Zhong¹,

Chen

et al. 2020

Oncol Lett

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Approximately 500,000 new head and neck squamous cell carcinoma (HNSCC) cases are detected every year around the world, and its incidence ranks sixth among all cancer types globally. Among these cases, oral squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC) are HNSCC subtypes with high incidence rates, especially in China. The present study examines the association between the apolipoprotein L1 (APOL1) mRNA and protein expression and clinical parameters in HNSCC. The two most common types (oral and larynx) of HNSCC were selected for subgroup analyses. Immunohistochemistry (IHC) was used to detect APOL1 protein expression levels in HNSCC clinical specimens. It was demonstrated that APOL1 protein expression in 221 cases of HNSCC was higher compared with that in normal tissues. Consistent upregulation of APOL1 protein was also found in subgroups of OSCC and LSCC. Through mining the ArrayExpress, The Cancer Genome Atlas and the Gene Expression Omnibus databases, microarrays and RNA sequencing data for HNSCC were retrieved, which were used to analyze APOL1 mRNA expression levels. The results showed that APOL1 expression was higher in both OSCC and LSCC subtypes, as well as in HNSCC, compared with that in non-cancerous squamous epithelium. The summary receiver operating characteristic analysis showed that APOL1 had potential as a diagnostic biomarker for HNSCC, OSCC and LSCC. Thus, upregulation of APOL1 may contribute to the tumorigenesis of HNSCC.

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“…So far, majority of studies focused on the exploration of AS events as biomarker for cancers have demonstrated that several AS events and spliced variants could be indicators to diagnose and predict cancers. For example, Kelley et al revealed that the aberrant splicing expression of GSN gene had an obviously higher expression in tumor tissues than in adjacent tissues and regulated the HNSCC's cell proliferation process [31]. Recently, a report suggested that KRAS-4A and KRAS-4B (KRAS isoforms) had signi cantly related to poor survival of CRC patients, especially microsatellite stable primary CRC [32].…”

Section: Discussionmentioning

confidence: 99%

Development of alternative splicing signature in lung squamous cell carcinoma

Yan

Liu

et al. 2021

Preprint

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Increasing evidence demonstrated that alternative splicing (AS) played a vital role in tumorigenesis and clinical outcome of patient. However, systematically analysis of AS in lung squamous cell carcinoma (LUSC) is lacking and greatly necessary. Thus, this study was to systematically estimate the function of AS events served as prognostic indicators in LUSC. Among 31,345 mRNA AS events in 9,633 genes, we detected 1,996 AS in 1,409 genes which have significantly connection with overall survival (OS) of LUSC patients. Then, prognostic model based on seven types of AS events were established and we further constructed a combined prognostic model. The Kaplan-Meier curve results suggested that seven types of AS signatures and the combined prognostic model could exhibit robust performance in predicting prognosis. Patients in the high risk group had significantly shorter OS than those in the low risk group. The ROC showed all prognostic models had high accuracy and powerful predictive performance with different AUC ranging from 0.837 to 0.978. Moreover, the combined prognostic model had highest performance in risk stratification and predictive accuracy than single prognostic models. Finally, a significant correlation network between survival-related AS genes and prognostic splicing factors (SFs) was established. In conclusion, our study provided several potential prognostic AS models and constructed splicing network between AS and SFs in LUSC, which could be used as potential indicators and treatment targets for LUSC patients.

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Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma

Cited by 11 publications

References 42 publications

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

Development of alternative splicing signature in lung squamous cell carcinoma

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