Journal Article

Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma

Buettner, Reinhard, Bruns, Christiane, Essakly, Ahlem, Bork, Julian, Hillmer, Axel M., Schroeder, Wolfgang, Alakus, Hakan, Schallenberg, Simon, Loeser, Heike, Zander, Thomas, Gebauer, Florian, Quaas, Alexander

2020

Overview

Background The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar members of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC). Methods We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data. Results Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2–139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7–19.1 months) in cases of ARIDA-1A loss ( p  = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2). Conclusion Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Adenocarcinoma / Adenosine triphosphatase / AKT protein / Antibodies / ATPases / Biomedical and Life Sciences / Biomedicine / BRG1 protein / c-Myc protein / Cancer Research / Cancer therapies / Cell cycle / Chemotherapy / Chromatin / Deoxyribonucleic acid / DNA / ErbB-2 protein / Esophageal cancer / Esophagus / Experimental therapeutics and drug development / Future predictions / Gene amplification / Genes / Genetic aspects / Health aspects / Health Promotion and Disease Prevention / Heterogeneity / Immunohistochemistry / Loss-of-function / Medical prognosis / Medicine/Public Health / Microsatellite instability / Mutation / Myc protein / Oesophageal adenocarcinoma / Oncology / p53 Protein / Patients / Poly(ADP-ribose) polymerase / Proteins / Research Article / Surgical Oncology / Survival / Survival analysis / SWI/SNF complex / Therapeutic applications / Time / TP53 loss / Tumor proteins / Tumors