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Cited by 3Glioma Diagnosis and TreatmentCancer Immunotherapy and BiomarkersCancer Genomics and Diagnostics

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Somatic Mutations in HLA Class Genes and Antigen-Presenting Molecules in Malignant Glioma

Schulte, Sara C., Peter, Wolfgang, Rosenberger, Georg, Schäfer, Moritz, Maire, Cecile L., Rünger, Alessandra, Ryba, Alice, Riecken, Kristoffer, Fita, Krystian D., Matschke, Jakob, Akyüz, Nuray, Dierlamm, Judith, Klau, Gunnar W., Ricklefs, Franz L., Gempt, Jens, Westphal, Manfred, Lamszus, Katrin, Dilthey, Alexander, Mohme, Malte·2025·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-24-0419

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Abstract

Immune evasion is a hallmark of gliomas, yet the genetic mechanisms by which tumors escape immune surveillance remain incompletely understood. In this study, we systematically examined the presence of somatic mutations in HLA genes and genes encoding proteins involved in antigen presentation across isocitrate dehydrogenase wild-type and mutant gliomas using targeted next-generation sequencing. To address the challenges associated with detecting somatic mutations in these highly polymorphic and complex regions of the genome, we applied a combination of short-read and long-read sequencing techniques, extended the genetic region of interest (exons and introns), and applied a tailored bioinformatics analysis pipeline, which enabled an accurate evaluation of comprehensive sequencing data. Our analysis identified mutations in HLA class II and nonclassic HLA genes as well as genes associated with antigen presentation, such as TAP1/2 and B2M. Three-dimensional modeling of individual mutations simulated the potential impact of somatic mutations in TAP1 and B2M on the encoded protein configuration. The presence of somatic mutations supports the role of antigen-presenting genes in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma, potentially resulting from a positive selection or mutagenic enrichment of tumor cells during tumor progression. Taken together, this research generates new insights and hypotheses for the functional analysis and optimization of immunotherapy strategies for gliomas, which may guide personalized treatment paradigms.

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Metadata

Authors
Schulte, S. C., Peter, W., Rosenberger, G., Schäfer, M., Maire, C. L., Rünger, A., Ryba, A., Riecken, K., Fita, K. D., Matschke, J., Akyüz, N., Dierlamm, J., Klau, G. W., Ricklefs, F. L., Gempt, J., Westphal, M., Lamszus, K., Dilthey, A., & Mohme, M.
Affiliations
  • Düsseldorf University Hospital (DE)
  • University of Cologne (DE)
  • University Medical Center Hamburg-Eppendorf (DE)
  • 4Stefan Morsch Stiftung, Birkenfeld, Germany.
  • 7Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Heinrich Heine University Düsseldorf (DE)
  • Universität Hamburg (DE)
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2025-05-05
Volume
13
Issue
7
Pages
1111-1123
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-24-0419
OpenAlex
W4410091406
Cited by
3
References
4
Citations by year
2026: 1 · 2025: 2
FWCI
1.92
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Bundesministerium für Bildung und Forschung (01EO2106)
  • Jürgen Manchot Foundation (428994620)
  • Deutsche Forschungsgemeinschaft (MO4183, RO 3660/7)
  • Anni Hofmann Foundation
Topics
  • Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords
somatic mutations, HLA class II genes, HLA class I genes, antigen presentation, high-grade glioma, glioblastoma, immune evasion, IDH mutation, TAP1, TAP2, beta2-microglobulin, recurrent glioblastoma, cancer immunotherapy, protein structure modeling
MeSH terms
ATP Binding Cassette Transporter, Subfamily B, Member 2, Brain Neoplasms, Glioma, HLA Antigens, Humans, Isocitrate Dehydrogenase, Mutation, Antigen Presentation, Computational Biology, High-Throughput Nucleotide Sequencing

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