Prognostic Bone Metastasis-Associated Immune-Related Genes Regulated by Transcription Factors in Mesothelioma

Our plain-English summary of Prognostic Bone Metastasis-Associated Immune-Related Genes Regulated by Transcription Factors in Mesothelioma, by Z. Hao, S. Wang, Z. Zheng, et al (BioMed Research International, 2022).

The study

• Authors: Z. Hao, S. Wang, Z. Zheng, J. Li, W. Fu, D. Han, Y. Huang, Q. Lin, S. Xian, P. Yan, M. Li, R. Lin, T. Meng, J. Zhang, Z. Huang
• Journal: BioMed Research International
• Published: 2022;2022:9940566
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma (MESO) is a mesothelial originate neoplasm with high morbidity and mortality. Despite advancement in technology, early diagnosis still lacks effectivity and is full of pitfalls. Approaches of cancer diagnosis and therapy utilizing immune biomarkers and transcription factors (TFs) have attracted more and more attention. But the molecular mechanism of these features in MESO bone metastasis has not been thoroughly studied. Utilizing high-throughput genome sequencing data and lists of specific gene subsets, we performed several data mining algorithm. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to identify downstream immune cells. Potential pathways involved in MESO bone metastasis were identified using Gene Oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and Cox regression analysis. Ultimately, a model to help early diagnosis and to predict prognosis was constructed based on differentially expressed immune-related genes between bone metastatic and nonmetastatic MESO groups. In conclusion, immune-related gene SDC2, regulated by TFs TCF7L1 and POLR3D, had an important role on immune cell function and infiltration, providing novel biomarkers and therapeutic targets for metastatic MESO.

Copyright © 2022 Zhiquan Hao et al.

In plain English

This was a computer analysis of public tumor gene-activity data (The Cancer Genome Atlas), plus a small tissue-staining check. The authors compared mesothelioma tumors from 4 patients whose cancer had spread to bone with 83 whose cancer had not. Of immune-related genes differing between the groups, 14 were linked to survival and combined into a risk score. The score had an accuracy measure (AUC) of 0.778. In single-factor analysis, bone metastasis (hazard ratio 3.654; confidence interval 1.292 to 10.329) and the risk score (hazard ratio 1.160; confidence interval 1.088 to 1.235) were associated with worse survival. In multi-factor analysis, the authors reported that the risk score remained a risk factor. SDC2 gene activity was correlated with the activity of four transcription-factor genes (genes that control other genes), including TCF7L1 (R = 0.7). In tissue from a few patients, staining for SDC2 and TCF7L1 was more intense in bone-metastatic cases. The authors concluded that SDC2 might play a role in bone metastasis and prognosis. They noted a small sample, possibly inexact database records, and cases from western countries. Asbestos exposure was not studied.

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: Bioinformatics (data-mining) analysis of public gene-expression and clinical data, with a small immunohistochemistry (tissue staining) check and analysis of public ATAC-seq data
• Who was studied: Mesothelioma patients in the TCGA database: 4 with bone metastasis and 83 without. The results and Table 1 give 87 patients, the methods give 86, and 84 had complete clinical information for the model analyses. The site of mesothelioma (pleural, peritoneal) is not specified. The authors state the cases were from western countries. Tissue staining used samples from 5 patients for SDC2 (3 bone-metastatic, 2 nonmetastatic) and 6 for TCF7L1 (3 and 3).
• Exposure: No asbestos or fiber exposure was studied. The comparison was between mesothelioma with bone metastasis and mesothelioma without bone metastasis, using gene activity data.
• Main results:
  • 14 immune-related genes that differed between bone-metastatic and nonmetastatic tumors were significantly associated with prognosis in univariate Cox regression.
  • The prognostic risk-score model had an area under the ROC curve (AUC) of 0.778, which the authors called good predictive power.
  • Patients with a high risk score had poorer survival in Kaplan-Meier analysis.
  • In univariate Cox regression, bone metastasis was reported as a risk factor for prognosis, with hazard ratio 3.654 (confidence interval 1.292 to 10.329) in Figure 4(f). The text reports HR = 3.65 with P = 0.020, while the figure gives P = 0.015. Only 4 patients had bone metastasis.
  • In univariate Cox regression, the risk score was reported as a risk factor for prognosis, with hazard ratio 1.160 (confidence interval 1.088 to 1.235) and P less than 0.001 in Figure 4(f).
  • In multivariate Cox regression, the authors reported that the risk score was an independent risk factor.
  • In correlation analysis of gene-expression data, expression of 4 of the 5 differentially expressed transcription-factor genes (RCOR1, TCF7L1, POLR3D, NR2F2) was correlated with expression of the same immune-related gene, SDC2.
  • TCF7L1 expression was positively correlated with SDC2 expression (P less than 0.001, R = 0.7 as printed in Figure 8(e); the text prints the same value as '0:700', with a colon in place of the decimal point).
  • M2 macrophages, resting dendritic cells and plasma cells were significantly associated with SDC2 (correlations 0.328, 0.233 and 0.227 in Figure 6).
  • In the tissue staining, SDC2 and TCF7L1 staining was more intense in bone-metastatic than nonmetastatic mesothelioma tissue (P < 0.05, Welch's t-test). This was based on 3 bone-metastatic vs 2 nonmetastatic samples for SDC2 and 3 vs 3 for TCF7L1.
• The authors' conclusion: The authors concluded that their model, based on bone metastasis-correlated immune-related genes, showed good predictive power for prognosis. They also concluded that the hub gene SDC2, regulated by specific transcription factors, might play an important role in bone metastasis and prognosis of mesothelioma by regulating immune cells.
• Limitations the authors state:
  • Data came from a public database that contained some inexact records.
  • The mesothelioma sample size in TCGA was relatively small.
  • The analysis was mostly mathematical, and more verification at the tissue and cell level is needed.
  • Cases were from western countries, so the conclusions may not apply to patients from elsewhere, such as Asian patients.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Metastasis, Mesothelioma, Neoplasm, Biomarker, Prognosis.

Related studies

• Identification of prognostic and bone metastasis​-related alternative splicing signatures in mesothelioma — R. Huang, Z. Zheng, et al. (2021)
• Development of a prognostic nomogram for patients with malignant mesothelioma with bone metastasis — A. Yang, B. Tang, et al. (2023)
• The Construction and Analysis of ceRNA Network and Patterns of Immune Infiltration in Mesothelioma With Bone Metastasis — R. Huang, J. Wu, et al. (2019)
• Ectopic pleural thymoma with T-cell lymphocytosis and bone metastasis: a case report — J. Li, L. Liu, et al. (2024)
• Diffuse pleural mesothelioma with distant bone metastasis. A case report — R.N. Laurini (1974)
• Inhibitors of the Transcription Factor STAT3 Decrease Growth and Induce Immune Response Genes in Models of Malignant Pleural Mesothelioma (MPM) — M. Lapidot, A.E. Case, et al. (2020)

Browse more research in BioMed Research International, or return to medical research.