Somatic mutations in HLA class genes and antigen presenting molecules in malignant glioma

In this study, we systematically examined the presence of somatic mutations in human leukocyte antigen (HLA) and antigen-presenting genes 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, we applied a combination of short-read and long-read sequencing techniques, an extended genetic region of interest (exons and introns), and 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 further shows the impact of somatic mutations in TAP1 and B2M on their functional properties during antigen presentation. These findings support the presence of somatic mutations in antigen-presenting genes and their role in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma (GBM), suggesting an evolutionary trajectory of tumor cells that potentially facilitates immune evasion in the post-treatment tumor microenvironment. Taken together, this research supports the use of genetic insights to inform the development and optimization of immunotherapy strategies for gliomas, potentially guiding personalized treatment paradigms. We provide matching normal and tumor sequencing data for each found somatic mutation. The sample names have the format normalID_tumorID_gene_[normal|tumor], where normalID and tumorID are used in the filenames of the normal and tumor fastq files, respectively. The gene refers to the HLA locus, e.g. C refers to HLA-C. The last part, [normal|tumor], indicates whether the reads originate from tumor tissue (tumor) or from citrate blood (normal).