Latest MCP Insights: Molecular Subtyping of Diffuse Gliomas from Genes to Proteins

Jingjie Academic/Selected

Diffuse Glioma is the most common primary central nervous system tumor in adults, which can be classified into astrocytoma, oligodendroglioma, and oligoastrocytoma, with a pathological grade of II to IV. Based on mutations in isocitrate dehydrogenase genes (IDH1/2) and the presence of co-deletion of chromosome arms 1p and 19q (1p19q codel), diffuse gliomas are primarily divided into three subtypes: (i) IDH-wildtype (IDHwt) astrocytoma; (ii) IDH-mutant (IDHmt) astrocytoma; and (iii) IDHmt, 1p19q co-deleted oligodendroglioma.

Currently, research on the molecular characteristics of diffuse gliomas mainly focuses on genomics and transcriptomics. However, an increasing number of studies have found that many tumor patients lack clear “Driver Mutations”, and simple genomic and transcriptomic information is insufficient to reflect the full picture of tumorigenesis and progression. Proteins, as biological macromolecules that execute biological functions, their changes and post-translational modifications directly affect various physiological or pathological states. Understanding the protein characteristics in different glioma subtypes can aid in developing personalized therapeutic targets, providing new directions for targeted therapy.

On July 28, the top journal in the field of proteomicsMCP published online the latest research findings on diffuse gliomas by Professor Phedias Diamandis from the Department of Experimental Medicine and Pathology at the University of Toronto. The researchers expanded the existing glioma proteomics resources using quantitative proteomics technology, adding proteomic information for different genetic subtypes of diffuse gliomas. The study found differences in protein expression in different biological processes among diffuse gliomas of different genetic subtypes, providing research ideas and directions for subsequent studies.

Latest MCP Insights: Molecular Subtyping of Diffuse Gliomas from Genes to Proteins

Research Highlights

1.Quantitative Analysis of Proteomics in Different Glioma Subtypes

To study the differences in protein levels among different glioma subtypes, the researchers analyzed FFPE tumor tissues, frozen tumor tissues, and GSCs cell samples of different genotypes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) (sample strategy). Approximately 2,500 proteins were identified in each group of FFPE samples, while about 2,900 proteins were identified in each group of frozen tumor tissues and GSCs cell samples, with most protein IDs overlapping, resulting in a total of 5,496 proteins identified, thus expanding the existing glioma proteomics resources. FFPE and frozen tumor tissue samples showed high similarity in molecular functions, biological processes, and cellular components, while there were significant differences in protein expression patterns among different genotypes (Figure 1C, D).

Latest MCP Insights: Molecular Subtyping of Diffuse Gliomas from Genes to Proteins Figure 1. LC-MS/MS Analysis of Proteomic Differences among Glioma Subtypes

2. IDH Mutation Status Affects the Abundance of Proteins Related to Different Biological Processes

To investigate the protein and potential biological pathways that drive clustering differences among glioma molecular subtypes, the researchers performed clustering analysis on 287 differential proteins quantified by LFQ from FFPE samples of different subtype tumor tissues (Figure 2A), followed by GSEA analysis at the protein level to identify IDHwt subtype gliomas enriched in proteins related to invasion and epithelial-mesenchymal transition (EMT), while IDHmt subtype gliomas were mainly enriched in proteins involved in mRNA splicing (Figure 2C).

Latest MCP Insights: Molecular Subtyping of Diffuse Gliomas from Genes to Proteins Figure 2. The Effect of IDH Mutation Status on the Changes in Abundance of Proteins Related to Different Biological Processes

3. Some Proteins in GSCs Can Serve as Biomarkers for Diffuse Gliomas

The researchers inferred that proteins identified in primary tumor tissues and confirmed in GSCs could serve as biomarkers for diffuse gliomas and validated this. The results indicated that among the 287 differential proteins quantified by LFQ in FFPE samples from different subtype tumors, 170 proteins were also detected in GSCs, with a higher correlation of IDHwt GBM to IDHwt than IDHmt GSCs (Figure 3A, B).

In two cell models of collagenoma, some differential proteins showed positive correlations (including CLIC1 and PLOD3), which are primarily located in the endoplasmic reticulum and participate in stress responses to hormonal stimulation (Figure 3C, D). Among them, PLOD3 is mainly expressed in IDHwt gliomas and is expressed at lower levels in IDHmt glioma tissues (Figure 3E, F). Survival analysis results indicated that the expression levels of CLIC1 and PLOD3 significantly affect the 3-year survival rate of patients.

Figure 3. Some Proteins in Tumor Tissues and GSCs Show Consistent IDH Status-Dependent Abundance Differences

Conclusion: Currently, research on the molecular characteristics of diffuse gliomas still mainly focuses on genomics and transcriptomics. In this paper, the researchers expanded the existing glioma proteomics resources using quantitative proteomics technology, adding proteomic information for different genetic subtypes of diffuse gliomas.

The study found differences in protein expression in different biological processes among diffuse gliomas of different genetic subtypes, with different IDH mutation statuses affecting the abundance of proteins related to different biological processes. When compared to GSCs with the same IDH status, relevant proteins (such as chloride intracellular channel 1, CLIC1, and EMT-related protein PLOD3) were identified.

In summary, this study provides potential personalized treatment options by comparing protein expression levels among different glioma subtypes, and offers potential targets for clinical treatment of diffuse gliomas, which is of significant guiding importance.

References:

Ugljesa Djuric, et al. (2019) Defining protein pattern differences among molecular subtypes of diffuse gliomas using mass spectrometry. Molecular & Cellular Proteomics.

This article is original by Jingjie Academic team, welcome to share it to your friend circle. For reprints, submissions, and other cooperation needs, please add WeChat ptm-market for consultation.

Past Highlights Review

4D-LFQ: New Generation! 4D Proteomics 2019 Highlights

Clinical Oncology: Review: Proteomics Studies of Large Sample Cohorts in Clinical Oncology

Neuroepithelial Tumors::Cancer Cell: Combined Analysis of Proteomics and Modifications Reveals Molecular Typing of Neuroepithelial Tumors

Gastric Cancer Molecular Typing: The Phoenix Rests on the Parasol, Not Stopping—Chinese Scholars Use Proteomics for Molecular Typing of Gastric Cancer and Reveal Potential Therapeutic Targets

Liver Cancer: The Beauty of Flowers and the Phoenix Flying, Nature| Chinese Human Proteome Project Discovers New Targets for Precision Treatment of Liver Cancer

Ovarian Cancer:CELL Heavyweight! Proteomics Reveals Chemosensitivity Mediators and Immunotherapy Targets in Ovarian Cancer

Pancreatic Cancer: Nature | Integrated Proteomics Research Reveals New Targets for Treating the “King of Cancer”

Breast Cancer: Nat Comun| Proteogenomics Reveals Targets for Drug Treatment of Breast Cancer

Lymphoma: PNAS | Proteogenomics Reveals Biomarkers and Potential Drug Targets for Lymphoma

Melanoma:CANCER RES: Targeted Quantitative Proteomics Reveals the “Murderers” of Melanoma Metastasis

Glioma: Arrow Without Missing—Using Multi-Omics to Identify Molecular Markers of Malignant Gliomas

Latest MCP Insights: Molecular Subtyping of Diffuse Gliomas from Genes to Proteins

Leave a Comment Cancel reply