Rabbit Anti-ARID1A monoclonal antibody, clone KK10-12

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 60.1months (95%CI 1.2-139.9months)] in patients with ARIDA-1A expression and 26.2months (95%CI 3.7-19.1months) 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.

Eukaryotic cells use histone modifiers and chromatin remodellers to facilitate protein DNA interactions in the nucleus; an important requisite for regulating several cardinal nuclear processes including transcription, replication, DNA repair and recombination, etc. The SWI/SNF complex is the most well-studied chromatin remodeller and is conserved from yeast to mammals. The complex is recruited to specific DNA sites, where it uses energy from ATP hydrolysis to catalyse nucleosome sliding or histone eviction from DNA. Mutational inactivation of SWI/SNF components has been identified in neurological syndromes and in several cancers. Recent deep sequencing studies have revealed a SWI/SNF mutation frequency of 20% in cancer genomes. In addition to mutations in tumour samples, extensive studies on cell lines and animal models have revealed tumour suppressive features for many individual SWI/SNF components. Thus, components of the complex are classified as tumour suppressors. Interestingly, however, majority of mutations cause incomplete inactivation of the complex, leaving behind a 'residual' complex that can be targeted for therapy. In addition, characterization of multiple roles of SWI/SNF components has revealed several therapeutic options. The current review summarizes the multi-faceted therapeutic opportunities for tumour bearing mutations in genes, encoding SWI/SNF components.