Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma
Abstract 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 (B...
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| Format: | Article |
| Language: | English |
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BMC
2020-01-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-019-6425-3 |
| _version_ | 1818866119270727680 |
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| author | Simon Schallenberg Julian Bork Ahlem Essakly Hakan Alakus Reinhard Buettner Axel M. Hillmer Christiane Bruns Wolfgang Schroeder Thomas Zander Heike Loeser Florian Gebauer Alexander Quaas |
| author_facet | Simon Schallenberg Julian Bork Ahlem Essakly Hakan Alakus Reinhard Buettner Axel M. Hillmer Christiane Bruns Wolfgang Schroeder Thomas Zander Heike Loeser Florian Gebauer Alexander Quaas |
| author_sort | Simon Schallenberg |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T10:58:22Z |
| format | Article |
| id | doaj.art-e10e4a042e8d4a9caa143e89f259d80d |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-19T10:58:22Z |
| publishDate | 2020-01-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj.art-e10e4a042e8d4a9caa143e89f259d80d2022-12-21T20:24:44ZengBMCBMC Cancer1471-24072020-01-0120111210.1186/s12885-019-6425-3Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinomaSimon Schallenberg0Julian Bork1Ahlem Essakly2Hakan Alakus3Reinhard Buettner4Axel M. Hillmer5Christiane Bruns6Wolfgang Schroeder7Thomas Zander8Heike Loeser9Florian Gebauer10Alexander Quaas11Institute of Pathology, University of CologneInstitute of Pathology, University of CologneInstitute of Pathology, University of CologneDepartment of General, Visceral and Cancer Surgery, University of CologneInstitute of Pathology, University of CologneInstitute of Pathology, University of CologneDepartment of General, Visceral and Cancer Surgery, University of CologneDepartment of General, Visceral and Cancer Surgery, University of CologneDepartment I of Internal Medicine, Center for Integrated Oncology (CIO)University of CologneInstitute of Pathology, University of CologneDepartment of General, Visceral and Cancer Surgery, University of CologneInstitute of Pathology, University of CologneAbstract 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.https://doi.org/10.1186/s12885-019-6425-3SWI/SNF-complexLoss-of-functionOesophageal adenocarcinomaTP53 lossHeterogeneity |
| spellingShingle | Simon Schallenberg Julian Bork Ahlem Essakly Hakan Alakus Reinhard Buettner Axel M. Hillmer Christiane Bruns Wolfgang Schroeder Thomas Zander Heike Loeser Florian Gebauer Alexander Quaas Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma BMC Cancer SWI/SNF-complex Loss-of-function Oesophageal adenocarcinoma TP53 loss Heterogeneity |
| title | Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma |
| title_full | Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma |
| title_fullStr | Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma |
| title_full_unstemmed | Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma |
| title_short | Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma |
| title_sort | loss of the swi snf atpase subunit members smarcf1 arid1a smarca2 brm smarca4 brg1 and smarcb1 ini1 in oesophageal adenocarcinoma |
| topic | SWI/SNF-complex Loss-of-function Oesophageal adenocarcinoma TP53 loss Heterogeneity |
| url | https://doi.org/10.1186/s12885-019-6425-3 |
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