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SWI/SNF Alterations in Squamous Bladder Cancers
Fabian Achenbach1, Michael Rose1, Nadina Ortiz-Brüchle1
1Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Abstract:
Dysfunction of the SWI/SNF complex has been observed in various cancers including urothelial carcinomas. However, the clinical impact of the SWI/SNF complex in squamous-differentiated bladder cancers (sq-BLCA) remains unclear. Therefore, we aimed to analyze potential expression loss and genetic alterations of (putative) key components of the SWI/SNF complex considering the co-occurrence of genetic driver mutations and PD-L1 expression as indicators for therapeutic implications. Assessment of ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2 and PBRM1 mutations in a TCGA data set of sq-BLCA (n = 45) revealed that ARID1A was the most frequently altered SWI/SNF gene (15%) while being associated with protein downregulation. Genetic alterations and loss of ARID1A were confirmed by Targeted Next Generation Sequencing (NGS) (3/6) and immunohistochemistry (6/116). Correlation with further mutational data and PD-L1 expression revealed co-occurrence of ARID1A loss and TP53 mutations, while positive correlations with other driver mutations such as PIK3CA were not observed. Finally, a rare number of sq-BLCA samples were characterized by both ARID1A protein loss and strong PD-L1 expression suggesting a putative benefit upon immune checkpoint inhibitor therapy. Hence, for the first time, our data revealed expression loss of SWI/SNF subunits in sq-BLCA, highlighting ARID1A as a putative target of a small subgroup of patients eligible for novel therapeutic strategies.
Insights
SWI/SNF complex gene loss, particularly ARID1A, is identified in squamous-differentiated bladder cancers (sq-BLCA). This finding suggests ARID1A as a potential therapeutic target for a subset of patients, especially those with co-occurring TP53 mutations and PD-L1 expression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- SWI/SNF complex dysfunction is implicated in various cancers.
- The role of SWI/SNF complex alterations in squamous-differentiated bladder cancer (sq-BLCA) is not well understood.
- Investigating these alterations may reveal therapeutic implications.
Purpose of the Study:
- To analyze SWI/SNF complex component expression loss and genetic alterations in sq-BLCA.
- To explore the co-occurrence of these alterations with driver mutations and PD-L1 expression.
- To identify potential therapeutic targets in sq-BLCA.
Main Methods:
- Analysis of SWI/SNF gene mutations (ARID1A, SMARCA2, SMARCA4, SMARCB1/INI1, SMARCC1, SMARCC2, PBRM1) in a TCGA dataset of sq-BLCA (n=45).
- Confirmation of ARID1A alterations using Targeted Next Generation Sequencing (NGS) and immunohistochemistry.
- Correlation analysis with driver mutations (e.g., TP53, PIK3CA) and PD-L1 expression.
Main Results:
- ARID1A was the most frequently altered SWI/SNF gene (15%) in sq-BLCA, associated with protein downregulation.
- ARID1A loss was confirmed by NGS and immunohistochemistry.
- ARID1A loss showed co-occurrence with TP53 mutations but not PIK3CA mutations.
- A subset of sq-BLCA exhibited both ARID1A protein loss and strong PD-L1 expression.
Conclusions:
- Expression loss of SWI/SNF subunits, notably ARID1A, occurs in sq-BLCA.
- ARID1A is a potential therapeutic target for a subgroup of sq-BLCA patients.
- The co-occurrence of ARID1A loss and PD-L1 expression suggests potential benefit from immune checkpoint inhibitor therapy.
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