Abstract
BackgroundThe 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).MethodsWe 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.ResultsLoss 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).ConclusionOur 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.
Highlights
The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%
Out of 685 patients with EAC, 560 patients were analysable for AT-rich interactive domain-containing protein 1A (ARID1A) and INI1 (81.8%), 563 patients for BRG1 (82.2%) and 578 patients (84.4%) for BRM
Tumours with ARID1A loss or expression and TP53 loss were not associated with a difference in survival
Summary
The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. 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). The overall survival has remained almost unchanged in recent years For these reasons, new biomarkers are needed that can contribute to a better understanding of tumor biology in specific subgroups of the adenocarcinomas of the esophagus. New biomarkers are needed that can contribute to a better understanding of tumor biology in specific subgroups of the adenocarcinomas of the esophagus This is associated with the hope of being able to personalise the treatment of specific tumour subgroups. There is reason to believe that adenocarcinomas of the oesophagus that show a loss of function of the SWI/SNF complex may represent such a tumor subgroup, as discussed later. An important goal of this study is how often a loss of the SWI/SNF complex and its individual functional protein components is found in a very large collective of oesophageal adenocarcinomas and what other molecular characteristics this SWI/SNF-loss subgroup has
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