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

BMC Cancer. 2020 Jan 6;20(1):12. doi: 10.1186/s12885-019-6425-3.

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.

Keywords: Heterogeneity; Loss-of-function; Oesophageal adenocarcinoma; SWI/SNF-complex; TP53 loss.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenosine Triphosphatases / genetics*
  • Adenosine Triphosphatases / metabolism
  • Aged
  • Biomarkers, Tumor / analysis
  • Chromatin Assembly and Disassembly
  • Cohort Studies
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / mortality
  • Esophageal Neoplasms / pathology
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Loss of Function Mutation
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Prognosis
  • SMARCB1 Protein / genetics
  • SMARCB1 Protein / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • ARID1A protein, human
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Nuclear Proteins
  • SMARCA2 protein, human
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Adenosine Triphosphatases
  • SMARCA4 protein, human
  • DNA Helicases

Supplementary concepts

  • Adenocarcinoma Of Esophagus