Schulte, Peter, and Rosenberger et al. evaluated IDH-mutant and wild-type gliomas for mutations in 16 genes encoding proteins involved in antigen presentation (HLAs and HLA-related proteins) using a bioinformatics pipeline specifically designed to detect mutations in these highly polymorphic genetic regions. This effectively identified somatic mutations in genes encoding HLA-II, nonclassical HLA genes, TAP1/2, and B2M. 3D modeling of non-synonomous mutations in TAP1 and B2M demonstrated that such mutations could disrupt antigen presentation, potentially mediating escape from T cells. Mutations were found to be more frequent in recurrent glioblastomas.
Contributed by Lauren Hitchings
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 human leukocyte antigen (HLA) genes and genes encoding proteins involved in antigen-presentation across isocitrate dehydrogenase wild-type (IDHwt) and mutant (IDHmut) gliomas using targeted next-generation sequencing (NGS). 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 non-classical 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 (GBM), 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.
Author Info: (1) Heinrich Heine University Dsseldorf, Dsseldorf, Germany. (2) Stefan-Morsch-Stiftung, Birkenfeld, Rheinland-Pfalz, Germany. (3) Institute of Human Genetics, University Medical
Author Info: (1) Heinrich Heine University Dsseldorf, Dsseldorf, Germany. (2) Stefan-Morsch-Stiftung, Birkenfeld, Rheinland-Pfalz, Germany. (3) Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Hamburg, Hamburg, Germany. (4) Stefan Morsch Stiftung, Birkenfeld, Germany, Germany. (5) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (6) Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Germany. (7) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (8) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (9) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (10) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (11) Hubertus Wald University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (12) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (13) Heinrich Heine University Dsseldorf, Dsseldorf, Germany. (14) University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany. (15) University Medical Center Hamburg-Eppendorf, Germany. (16) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (17) University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (18) Institute of Medical Microbiology and Hospital Hygiene, University Hospital Dsseldorf, Heinrich Heine University Dsseldorf, Dsseldorf, Germany, Germany. (19) University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
