SWI/SNF Alterations in Squamous Bladder Cancers

Genes, vol. 11, pp. 1368

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.

Authors 12

1. Fabian Achenbach Aachen Institute of Pathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

2. Michael Rose Aachen Institute of Pathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

3. Nadina Ortiz‐Brüchle Aachen Institute of Pathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

4. Lancelot Seillier Aachen Institute of Pathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

5. Ruth Knüchel Aachen Institute of Pathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

6. Veronika Weyerer

   Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

   Affiliation as printed

   Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany

7. Arndt Hartmann

   Friedrich-Alexander-Universität Erlangen-Nürnberg · Universitätsklinikum Erlangen

   Affiliation as printed

   Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany

8. Ronja Morsch Aachen Department of Urology

   RWTH Aachen University

   Affiliation as printed

   Department of Urology, RWTH Aachen University, 52074 Aachen, Germany

9. Angela Maurer Aachen Institute of Pathology

   RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

10. Thorsten Ecke

    Helios Hospital Bad Saarow

    Affiliation as printed

    Department of Urology, Helios Clinic, 15526 Bad Saarow, Germany

11. Stefan Garczyk Aachen Institute of Pathology

    RWTH Aachen University

    Affiliation as printed

    Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany

12. Nadine Therese Gaisa corresponding Aachen Institute of Pathology

    RWTH Aachen University

    Affiliation as printed

    Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany