Universität zu Köln

Schallenberg, Simon, Bork, Julian, Essakly, Ahlem, Alakus, Hakan, Buettner, Reinhard, Hillmer, Axel M., Bruns, Christiane, Schroeder, Wolfgang, Zander, Thomas, Loeser, Heike, Gebauer, Florian and Quaas, Alexander (2020). Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma. BMC Cancer, 20 (1). LONDON: BMC. ISSN 1471-2407

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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 60.1months (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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schallenberg, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Bork, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Essakly, Ahlem UNSPECIFIED UNSPECIFIED UNSPECIFIED Alakus, Hakan UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Hillmer, Axel M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Zander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Loeser, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Gebauer, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Quaas, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-349182
DOI:	10.1186/s12885-019-6425-3
Journal or Publication Title:	BMC Cancer
Volume:	20
Number:	1
Date:	2020
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1471-2407
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPSTEIN-BARR-VIRUS; MISMATCH-REPAIR; SOMATIC MUTATIONS; GASTRIC-CANCER; CELL-LINES; EXPRESSION; GENE; EXOME; COMPLEXES; PATHWAY Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34918