Clinicopathological Significance, Related Molecular Changes and Tumor Immune Response Analysis of the Abnormal SWI/SNF Complex Subunit PBRM1 in Gastric Adenocarcinoma

Abstract

Background: PBRM1 gene abnormalities were recently found to play a role in tumor development and tumor immune activity. This article will explore the clinicopathological and molecular changes and tumor immune activity of the abnormal SWI/SNF complex subunit PBRM1 in gastric adenocarcinoma (GAC) and its significance.Methods: The cBioPortal, LinkedOmics and TISIDB datasets were used to analyze the abnormality of the PBRM1 gene in GAC and its relationship with prognosis, related molecular changes and tumor-infiltrating lymphocytes (TILs). In addition, 198 GAC cases were collected to further study the relationship between the loss/attenuation of PBRM1 expression and clinicopathology, prognosis, microsatellite stability, PD-L1 expression and TIL in GAC. DNA whole-exome sequencing was performed on 7 cases of gastric cancer with loss of PBRM1 expression.Results: The cBioPortal data showed that PBRM1 deletion/mutation accounted for 7.32% of GAC and was significantly associated with several molecular changes, such as molecular subtypes of GAC. The LinkedOmics dataset showed that PBRM1 mutation and its promoter DNA methylation showed lower PBRM1 mRNA expression, and PBRM1 mutation cases showed significantly higher mRNA expression of PD-L1 (CD274). TISIDB data showed that PBRM1 abnormalities were significantly positively associated with multiple TILs. In our group of 198 cases, the loss/attenuation of PBRM1 expression was significantly positively correlated with intra-tumoral tumor infiltrating lymphocytes (iTILs) and deficient MMR and PD-L1 expression. Kaplan–Meier survival analysis showed that the overall survival of GAC patients with loss/attenuation of PBRM1 expression was significantly better (p = 0.023). iTIL was an independent prognostic factor of GAC. Loss of PBRM1 expression often co-occurs with mutations in other SWI/SNF complex subunit genes, and there are some repetitive KEGG signaling changes.Conclusion: Abnormality of the PBRM1 gene may be related to the occurrence of some GACs and can affect tumor immune activity, thereby affecting clinicopathology and prognosis. It may be a potentially effective predictive marker for immunotherapy and a novel therapeutic approach associated with synthetic lethality.

Advances in the role of SWI/SNF complexes in tumours

“…31 Furthermore, mutations in PBRM1 are also associated with pancreatic cancer (PDAC), advanced gastric cancer (GC), cervical cancer (CCA) and other tumour formation related. [32][33][34][35][36] [20][21][22][23][24][25][26][27][28][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] In addition, genes encoding tumour-associated subunits of the SWI/SNF complex, such as BAF57/SMARCE1, are heterozygous for mutations or completely lost in familial spinal meningioma cases. 31 Some of these tumours contain mutations in more than one subunit, such as renal cell carcinoma, breast cancer, and colon cancer, suggesting that the development of a cancer may be caused by mutations in one or more subunits of the SWI/ SNF complex.…”

“…PBRM1, a target subunit of PBAF, is a common oncogene with a 40% mutation rate in renal cell carcinoma, and our previous study found that deletion of PBRM1 could activate the AKT pathway and glycolytic pathway and thus affect the function of ccRCC cells 31 . Furthermore, mutations in PBRM1 are also associated with pancreatic cancer (PDAC), advanced gastric cancer (GC), cervical cancer (CCA) and other tumour formation related 32–36 . BRD7, SMARCC2, ARID2, ACTL6A/B, SMARCC1, SMARCD1/2/3 are other key subunits of SWI/SNF, and recent studies have reported that mutations in these subunits cause gastric cancer (GC), colon cancer (CRC), hepatocellular carcinoma (HCC), head and neck squamous carcinoma (HSNC), breast cancer (BRCA) and other tumours 20–28,37–53 .…”