Proteomics separates adult-type diffuse high-grade gliomas in metabolic subgroups independent of 1p/19q codeletion and across IDH mutational status

Bader, Jakob; Deigendesch, Nikolaus; Misch, Martin; Mann, Matthias; Koch, Arend; Meissner, Felix

doi:10.1016/j.xcrm.2022.100877

Cited by 6 publications

(7 citation statements)

References 159 publications

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“…To test whether neojunctions are translated into proteins, we analyzed mass spectrometry (MS) data derived from glioma patients (n=447) in multiple publicly available MS data sets. [53][54][55] Our analysis confirmed the detectable expression of unique neopeptides that map back to 302 (38.3%) unique public neojunctions (Figure 4C). We confirmed that these detected peptide sequences span the aberrantly spliced regions with sequence specific searches within the MS data and subsequent analysis of the resulting MS spectra (Figures S4I-J).…”

Section: Public Neojunctions Are Detectable On An Rna and Peptide Lev...supporting

confidence: 69%

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens

Kwok,

Stevers,

Nejo

et al. 2023

Preprint

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T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide. We identified CD8+ T-cell clones specific for neoantigens derived from tumor-wide and conserved neojunctions in GNAS and RPL22, respectively. TCR-engineered CD8+ T-cells targeting these mutations conferred neoantigen-specific tumor cell eradication. Furthermore, we revealed that cancer-specific dysregulation in splicing factor expression leads to recurrent neojunction expression. Together, these data reveal that a subset of neojunctions are both intratumorally conserved and public, providing the molecular basis for novel T-cell-based immunotherapies that address intratumoral heterogeneity.

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Section: Public Neojunctions Are Detectable On An Rna and Peptide Lev...supporting

confidence: 69%

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens

Kwok,

Stevers,

Nejo

et al. 2023

Preprint

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“…We propose that, given the primary role of proteins in executing physiological functions within organisms, a proteome-based approach may uncover signaling pathways that could pave the way for the development of innovative therapeutic strategies. Indeed, there is increasing evidence in the literature that supports the existence of distinct metabolic proteomic subtypes in glioblastoma based on aerobic/anaerobic energy metabolism [7,31].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling of Gliomas Unveils Immune and Metabolism-Driven Subtypes with Implications for Anti-Nucleotide Metabolism Therapy

Hua,

Zhang,

Sun

et al. 2024

Preprint

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Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made in glioma at the genomic and transcriptomic levels, comprehensive proteomic characterizations and their implications remain largely unexplored. Here, we performed proteogenomic characterization of gliomas using 343 FFPE tumor samples and 53 normal-appearing brain samples from 188 patients, which was integrated with genomic panel data and clinical information. Proteomics profiles uncovered two subgroups: Subgroup 1, termed the “metabolism subgroup” (S-Me), characterized by an enrichment of metabolism-related proteins; and Subgroup 2, named the “immune subgroup” (S-Im), showing an upregulation of immune and inflammatory proteins. These proteomic subgroups exhibited significant differences in prognosis, tumorigenesis, microenvironment dysregulation and potential therapeutics, emphasizing the critical roles of metabolism and immune processes in glioma biology and patient outcomes. By delving into metabolic pathways guided by our proteomic findings, DPYD and TYMP were further identified as potential prognostic biomarkers associated with nucleotide metabolic reprogramming. Functional validation using GSCs and animal models highlighted nucleotide metabolism as a promising therapy against gliomas. The integrated multi-omics analysis introduces a novel proteomic classification for gliomas, and also identified two new metabolic biomarkers, DPYD and TYMP, which offer insights into the molecular pathogenesis and identify treatment opportunities.

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“…In this issue, Bader et al. 1 describe proteomic and phospho-proteomic analyses of biopsies from 42 representative glioma biopsies with previously established IDH and codel statuses. 1 Consistent with their aneuploidies, IDH wild-type samples showed increased levels of chromosome 7-encoded proteins and decreased levels of chromosome 10-encoded proteins compared to IDH mutant tumors.…”

Section: Main Textmentioning

confidence: 99%

“… 1 describe proteomic and phospho-proteomic analyses of biopsies from 42 representative glioma biopsies with previously established IDH and codel statuses. 1 Consistent with their aneuploidies, IDH wild-type samples showed increased levels of chromosome 7-encoded proteins and decreased levels of chromosome 10-encoded proteins compared to IDH mutant tumors. Surprisingly, molecular relationship revealed that IDH -mutants could be divided into two unexpected entities that cluster independently of codel status.…”

Section: Main Textmentioning

confidence: 99%