Skip to main content

Advertisement

Log in

Expression of SMARCA2 and SMARCA4 in gastric adenocarcinoma and construction of a nomogram prognostic model

  • Original Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Aberrant expression of SWI/SNF complex subunits is closely associated with tumorigenesis. The clinicopathological and prognostic significance of altered SMARCA2 and SMARCA4 subunits has not been well evaluated in gastric adenocarcinoma.

Methods

We collected 1271 postoperative cases of gastric adenocarcinoma and then constructed tissue microarrays (TMA), from which we obtained the immunohistochemistry expression of SMARCA2 and SMARCA4. Next, we screened the variables related to the loss of SMARCA2 and SMARCA4 by univariate correlation analysis and multivariate logistic regression analysis. Then, we identified the variables related to prognosis by univariate and multivariate Cox regression analysis. Finally, we constructed a nomogram prognostic model and evaluated it.

Results

The loss of SMARCA2 and SMARCA4 occurred in 236 (18.57%) and 86 (6.77%) cases, respectively, including 26 cases of co-loss. After multivariate logistic regression, variables independently associated with SMARCA2 loss were T stage, differentiation status, WHO histological classification, and EBER. Variables independently associated with SMARCA4 loss were differentiation status, WHO histological classification, PD-L1, and MMR. Survival analysis revealed that the SMARCA2 and SMARCA4 lost groups showed worse survival than the corresponding present groups (P = 0.032 and P = 0.0048, respectively). Univariate and multivariate Cox analyses identified independent prognostic factors, including age, T stage, N stage, M stage, SMARCA2, and chemotherapy.

Conclusion

The loss of SMARCA2 and SMARCA4 correlated with poor differentiation, leading to a worse prognosis. SMARCA2, as an independent prognostic factor, combined with other clinicopathological variables, established a novel nomogram prognostic model, which outperformed the AJCC TNM model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets for this study are available from the corresponding author.

References

  1. Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  2. Zhang XY, Zhang PY (2017) Gastric cancer: somatic genetics as a guide to therapy. J Med Genet 54(5):305–312

    Article  CAS  PubMed  Google Scholar 

  3. Gao JP, Xu W, Liu WT et al (2018) Tumor heterogeneity of gastric cancer: from the perspective of tumor-initiating cell. World J Gastroenterol 24(24):2567–2581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Narlikar GJ, Sundaramoorthy R, Owen-Hughes T (2013) Mechanisms and functions of ATP-dependent chromatin-remodeling enzymes. Cell 154(3):490–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Clapier CR, Iwasa J, Cairns BR et al (2017) Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes. Nat Rev Mol Cell Biol 18(7):407–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alfert A, Moreno N, Kerl K (2019) The BAF complex in development and disease. Epigenetics Chromatin 12(1):19

    Article  PubMed  PubMed Central  Google Scholar 

  7. Mittal P, Roberts CWM (2020) The SWI/SNF complex in cancer - biology, biomarkers and therapy. Nat Rev Clin Oncol 17(7):435–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Centore RC, Sandoval GJ, Soares LMM et al (2020) Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies. Trends Genet 36(12):936–950

    Article  CAS  PubMed  Google Scholar 

  9. Huang SC, Ng KF, Chang IY et al (2021) The clinicopathological significance of SWI/SNF alterations in gastric cancer is associated with the molecular subtypes. PLoS ONE 16(1):e0245356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gluckstein MI, Dintner S, Arndt TT et al (2021) Comprehensive immunohistochemical study of the SWI/SNF complex expression status in gastric cancer reveals an adverse prognosis of SWI/SNF deficiency in genomically stable gastric carcinomas. Cancers (Basel) 13 (15)

  11. Chiba H, Muramatsu M, Nomoto A et al (1994) Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res 22(10):1815–1820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Reisman DN, Sciarrotta J, Bouldin TW et al (2005) The expression of the SWI/SNF ATPase subunits BRG1 and BRM in normal human tissues. Appl Immunohistochem Mol Morphol 13(1):66–74

    Article  CAS  PubMed  Google Scholar 

  13. Wang X, Sansam CG, Thom CS et al (2009) Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. Cancer Res 69(20):8094–8101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mardinian K, Adashek JJ, Botta GP et al (2021) SMARCA4: implications of an altered chromatin-remodeling gene for cancer development and therapy. Mol Cancer Ther 20(12):2341–2351

    Article  CAS  PubMed  Google Scholar 

  15. Xia QY, Zhan XM, Fan XS et al (2017) BRM/SMARCA2-negative clear cell renal cell carcinoma is associated with a high percentage of BRM somatic mutations, deletions and promoter methylation. Histopathology 70(5):711–721

    Article  PubMed  Google Scholar 

  16. Jancewicz I, Siedlecki JA, Sarnowski TJ et al (2019) BRM: the core ATPase subunit of SWI/SNF chromatin-remodelling complex-a tumour suppressor or tumour-promoting factor? Epigenetics Chromatin 12(1):68

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ouyang X, Ye XL, Wei HB (2017) BRM promoter insertion polymorphisms increase the risk of cancer: a meta-analysis. Gene 626:420–425

    Article  CAS  PubMed  Google Scholar 

  18. Bourachot B, Yaniv M, Muchardt C (2003) Growth inhibition by the mammalian SWI-SNF subunit Brm is regulated by acetylation. EMBO J 22(24):6505–6515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. La Rochelle J, Klatte T, Dastane A et al (2010) Chromosome 9p deletions identify an aggressive phenotype of clear cell renal cell carcinoma. Cancer 116(20):4696–4702

    Article  PubMed  Google Scholar 

  20. Puliga E, Corso S, Pietrantonio F et al (2021) Microsatellite instability in gastric cancer: between lights and shadows. Cancer Treat Rev 95:102175

    Article  PubMed  Google Scholar 

  21. Jelinic P, Ricca J, Van Oudenhove E et al (2018) Immune-active microenvironment in small cell carcinoma of the ovary, hypercalcemic type: rationale for immune checkpoint blockade. J Natl Cancer Inst 110(7):787–790

    Article  PubMed  PubMed Central  Google Scholar 

  22. Naito T, Umemura S, Nakamura H et al (2019) Successful treatment with nivolumab for SMARCA4-deficient non-small cell lung carcinoma with a high tumor mutation burden: a case report. Thorac Cancer 10(5):1285–1288

    Article  PubMed  PubMed Central  Google Scholar 

  23. Peng L, Li J, Wu J et al (2021) A pan-cancer analysis of SMARCA4 alterations in human cancers. Front Immunol 12:762598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guerrero-Martinez JA, Reyes JC (2018) High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer. Sci Rep 8(1):2043

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zhang Z, Wang F, Du C et al (2017) BRM/SMARCA2 promotes the proliferation and chemoresistance of pancreatic cancer cells by targeting JAK2/STAT3 signaling. Cancer Lett 402:213–224

    Article  CAS  PubMed  Google Scholar 

  26. Xu X, Zheng Z, Jia L et al (2018) Overexpression of SMARCA2 or CAMK2D is associated with cisplatin resistance in human epithelial ovarian cancer. Oncol Lett 16(3):3796–3804

    PubMed  PubMed Central  Google Scholar 

  27. Wu Q, Lian JB, Stein JL et al (2017) The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics 9(6):919–931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chang B, Sheng W, Wang L et al (2021) SWI/SNF complex-deficient undifferentiated carcinoma of the gastrointestinal tract: clinicopathologic study of 30 cases with an emphasis on variable morphology, immune features, and the prognostic significance of different SMARCA4 and SMARCA2 subunit deficiencies. Am J Surg Pathol

  29. Agaimy A, Daum O, Markl B et al (2016) SWI/SNF Complex-deficient undifferentiated/rhabdoid carcinomas of the gastrointestinal tract: a series of 13 cases highlighting mutually exclusive loss of SMARCA4 and SMARCA2 and frequent co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol 40(4):544–553

    Article  PubMed  Google Scholar 

  30. Karnezis AN, Wang Y, Ramos P et al (2016) Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. J Pathol 238(3):389–400

    Article  CAS  PubMed  Google Scholar 

  31. Herpel E, Rieker RJ, Dienemann H et al (2017) SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens. Ann Diagn Pathol 26:47–51

    Article  PubMed  Google Scholar 

  32. Ramalingam P, Croce S, McCluggage WG (2017) Loss of expression of SMARCA4 (BRG1), SMARCA2 (BRM) and SMARCB1 (INI1) in undifferentiated carcinoma of the endometrium is not uncommon and is not always associated with rhabdoid morphology. Histopathology 70(3):359–366

    Article  PubMed  Google Scholar 

  33. Chetty R, Serra S (2020) SMARCA family of genes. J Clin Pathol 73(5):257–260

    Article  CAS  PubMed  Google Scholar 

  34. Sun S, Li Q, Zhang Z et al (2022) SMARCA2 deficiency in NSCLC: a clinicopathologic and immunohistochemical analysis of a large series from a single institution. Environ Health Prev Med 27:3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kahali B, Gramling SJ, Marquez SB et al (2014) Identifying targets for the restoration and reactivation of BRM. Oncogene 33(5):653–664

    Article  CAS  PubMed  Google Scholar 

  36. Chan-Penebre E, Armstrong K, Drew A et al (2017) Selective killing of SMARCA2- and SMARCA4-deficient small cell carcinoma of the ovary hypercalcemic type cells by inhibition of EZH2: in vitro and in vivo preclinical models. Mol Cancer Ther 16 (5):850–860

  37. O’Neil NJ, Bailey ML, Hieter P (2017) Synthetic lethality and cancer. Nat Rev Genet 18(10):613–623

    Article  CAS  PubMed  Google Scholar 

  38. Shiraishi N, Sato K, Yasuda K et al (2007) Multivariate prognostic study on large gastric cancer. J Surg Oncol 96(1):14–18

    Article  PubMed  Google Scholar 

  39. Zhou ZR, Wang WW, Li Y et al (2019) In-depth mining of clinical data: the construction of clinical prediction model with R. Ann Transl Med 7(23):796

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

Study design: ZZ, SZ. Patient tissue collection: ZZ, SS, ZL, SX. Pathology review: SZ, ZZ, QJL. Supply of reagents: QL, YZ. Data analysis: ZZ, SS. Manuscript: ZZ. Manuscript review: SZ, ZGC.

Corresponding author

Correspondence to Shukun Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This study was approved by the Ethics Review Board of the Weihai Municipal Hospital (permission code: 2,021,053).

Informed consent

Informed consent was obtained from patients before enrollment in this study.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Z., Li, Q., Sun, S. et al. Expression of SMARCA2 and SMARCA4 in gastric adenocarcinoma and construction of a nomogram prognostic model. Int J Clin Oncol 28, 1487–1500 (2023). https://doi.org/10.1007/s10147-023-02403-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-023-02403-0

Keywords

Navigation