Dataset Information

The significance of SMARCB1 in the pathogenesis of renal cell carcinoma with rhabdoid features.

ABSTRACT:

Background

Renal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy.

Methods

Expression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay.

Results

Expression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro.

Conclusion

Inactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.

SUBMITTER: Wang YW

PROVIDER: S-EPMC8273225 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear-cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid clear-cell renal cell carcinoma. We assessed cancer-related mutations from eight cases using a clinical next-generation exome-sequencing platform. The transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid clear-cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear-cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear-cell renal cell carcinoma are often discordant across different morphologic regions, whereas the gene expression program is relatively stable. Molecular profiling of clear-cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions.

Project description:BackgroundRenal cell carcinoma (RCC) accounts for 90% of renal cancers, of which clear cell carcinoma (ccRCC) is the most usual histological type. The process of alternative splicing (AS) contributes to protein diversity, and the dysregulation of protein diversity may have a great influence on tumorigenesis. We developed a prognostic signature and comprehensively analyzed the role of tumor immune microenvironment (TIME) and immune checkpoint blocking (ICB) treatment in ccRCC.MethodsTo identify prognosis-related AS events, univariate Cox regression was used and functional annotation was performed using gene set enrichment analysis (GSEA). In this study, prognostic signatures were developed based on multivariate Cox, univariate Cox, and LASSO regression models. Moreover, to assess the prognostic value, the proportional hazards model, Kruskal-Wallis analysis, and ROC curves were used. To obtain a better understanding of TIME in ccRCC, the ESTIMATE R package, single sample gene set enrichment analysis (ssGSEA) algorithm, CIBERSORT method, and the tumor immune estimation resource (TIMER) were applied. The database was searched to verify the expression of C4OF19 in tumor and normal samples. Regulatory networks for AS-splicing factors (SFs) were visualized using Cytoscape 3.9.1.ResultsThere were 9,347 AS cases associated with the survival of ccRCC patients screened. A total of eight AS prognostic signatures were developed with stable prognostic predictive accuracy based on splicing subtypes. In addition, a qualitative prognostic nomogram was developed, and the prognostic prediction showed high effectiveness. In addition, we found that the combined signature was significantly associated with the diversity of TIME and ICB treatment-related genes. C4ORF19 might become an important prognostic factor for ccRCC. Finally, the AS-SF regulatory network was established to clearly reveal the potential function of SFs.ConclusionWe found novel and robust indicators (i.e., risk signature, prognostic nomogram, etc.) for the prognostic prediction of ccRCC. A new and reliable prognostic nomogram was established to quantitatively predict the clinical outcome. The AS-SF networks could provide a new way for the study of potential regulatory mechanisms, and the important roles of AS events in the context of TIME and immunotherapy efficiency were exhibited. C4ORF19 was found to be a vital gene in TIME and ICB treatment.