Pan-cancer analyses of bromodomain containing 9 as a novel therapeutic target reveals its diagnostic, prognostic potential and biological mechanism in human tumours

Our plain-English summary of Pan-cancer analyses of bromodomain containing 9 as a novel therapeutic target reveals its diagnostic, prognostic potential and biological mechanism in human tumours, by Y. Chen, Z. Gao, I. Mohd-Ibrahim, et al (Clinical and Translational Medicine, 2024).

The study

• Authors: Y. Chen, Z. Gao, I. Mohd-Ibrahim, H. Yang, L. Wu, Y. Fu, Y. Deng
• Journal: Clinical and Translational Medicine
• Published: 2024;14(2):e1543
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Mutations in one or more genes responsible for encoding subunits within the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodelling complexes are found in approximately 25% of cancer patients. Bromodomain containing 9 (BRD9) is a more recently identified protein coding gene, which can encode SWI/SNF chromatin-remodelling complexes subunits. Although initial evaluations of the potential of BRD9-based targeted therapy have been explored in the clinical application of a small number of cancer types, more detailed study of the diagnostic and prognostic potential, as well as the detailed biological mechanism of BRD9 remains unreported.

Methods: We used various bioinformatics tools to generate a comprehensive, pan-cancer analyses of BRD9 expression in multiple disease types described in The Cancer Genome Atlas (TCGA). Experimental validation was conducted in tissue microarrays and cell lines derived from lung and colon cancers.

Results: Our study revealed that BRD9 exhibited elevated expression in a wide range of tumours. Analysis of survival data and DNA methylation for BRD9 indicated distinct conclusions for multiple tumours. mRNA splicing and molecular binding were involved in the functional mechanism of BRD9. BRD9 may affect cancer progression through different phosphorylation sites or N6 -methyladenosine site modifications. BRD9 could potentially serve as a novel biomarker for diagnosing different cancer types, especially could accurately forecast the prognosis of melanoma patients receiving anti-programmed cell death 1 immunotherapy. BRD9 has the potential to serve as a therapeutic target, when pairing with etoposide in patients with melanoma. The BRD9/SMARCD1 axis exhibited promising discriminative performance in forecasting the prognosis of patients afflicted with liver hepatocellular carcinoma (LIHC) and mesothelioma. Additionally, this axis appears to potentially influence the immune response in LIHC by regulating the programmed death-ligand 1 immune checkpoint. For experimental validation, high expression levels of BRD9 were observed in tumour tissue samples from both lung and colon cancer patients. Knocking down BRD9 led to the inhibition of lung and colon cancer development, likely via the Wnt/β-catenin signalling pathway.

Conclusions: These pan-cancer study revealed the diagnostic and prognostic potential, along with the biological mechanism of BRD9 as a novel therapeutic target in human tumours.

© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

In plain English

This study did not examine asbestos. The authors analysed the gene BRD9 across many tumour types in public databases, mainly The Cancer Genome Atlas (TCGA), then tested it in lung and colon cancer tissue and cell lines. BRD9 was significantly higher in tumour than matched normal tissue in many cancers. Higher BRD9 expression was linked to worse overall survival in several cancers, including the TCGA mesothelioma (MESO) cohort. The article does not say if these were pleural or peritoneal. In the TCGA mesothelioma cohort, a risk score from BRD9 and its partner gene SMARCD1 separated longer from shorter overall survival. Its AUC values (how well the score told patients apart) were 0.671 (95% CI 0.567 to 0.775), 0.811 (0.733 to 0.889) and 0.746 (0.654 to 0.838) at 1, 3 and 5 years. PD-L1 expression there did not significantly correlate with either gene. Reducing BRD9 slowed growth and colony formation of lung and colon cancer cell lines. The authors concluded that BRD9 has diagnostic and prognostic potential as a treatment target. They noted that TCGA samples came from untreated patients.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Pan-cancer bioinformatics analysis of public databases, with laboratory validation in tissue microarrays and cell lines
• Who was studied: Tumour and normal samples from TCGA cancer cohorts (including a mesothelioma cohort, TCGA-MESO), plus tissue microarrays and cell lines from lung and colon cancers. The text does not give the size of the mesothelioma cohort.
• Main results:
  • Compared with matched adjacent normal samples, BRD9 was significantly upregulated in tumour tissue across various cancer types.
  • Elevated BRD9 expression was linked to adverse overall survival in the adrenocortical carcinoma, liver hepatocellular carcinoma, mesothelioma (MESO) and sarcoma cohorts.
  • In the TCGA-MESO cohort, the low-risk group based on the BRD9/SMARCD1 risk score had longer overall survival than the high-risk group.
  • In the TCGA-MESO cohort, the 1-, 3- and 5-year AUC values for the BRD9/SMARCD1 prognostic signature were 0.671 (95% CI 0.567 to 0.775), 0.811 (95% CI 0.733 to 0.889) and 0.746 (95% CI 0.654 to 0.838).
  • In the TCGA-MESO cohort, infiltration of B cells was positively correlated with the BRD9/SMARCD1 risk score.
  • In the TCGA-MESO cohort, PD-L1 expression did not show a significant correlation with BRD9 or SMARCD1 expression.
  • In lung and colon cancer cell lines, BRD9 knockdown suppressed proliferation (including the HT-29 and SW480 colon cancer cells) and inhibited colony formation.
• The authors' conclusion: The authors concluded that their pan-cancer study revealed the diagnostic and prognostic potential, and the biological mechanism, of BRD9 as a novel therapeutic target in human tumours.
• Limitations the authors state:
  • TCGA tumour samples came from untreated patients.
  • TCGA contains no immuno-oncology data.

Topics

Medical terms in this study, explained in our Lexicon: Targeted Therapy, Colorectal Cancer, Biomarker, Prognosis, Immunotherapy, Carcinoma, Mesothelioma.

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