{
  "abstract": "Background Thymic epithelial tumours (TETs) are rare, histologically diverse malignancies with limited treatment options and poorly characterised molecular drivers. Given the scarcity of biomarkers to guide immunotherapy in TETs, we conducted an integrative analysis to characterise immune phenotypes and identify actionable genomic and copy number alterations across different TET subtypes.Methods Three datasets were analysed:Immune-checkpoint expression (B7-H3, PD-L1, PD-1) via immunohistochemistry in 125 archival TET specimens.Retrospective analysis of Next Generation Sequencing (NGS) data, of FFPE-derived DNA from [n=5] TETs (TruSight Oncology 500 panel).N GS performed on FFPE-derived TET sample DNA from the KHP BioBank [n=6] using the OncoDEEP™ Kit panel.Results Immune profiling identified four checkpoint phenotypes across TET subtypes: immune ignorance (B7-H3 +, PD-L1−, PD-1−) was prevalent in type A and AB thymomas; tolerance (B7-H3+, PD-1+) was observed in B2 and B3 thymomas; evasion (B7-H3+, PD-L1+, PD-1+) associated with thymic carcinomas; and exclusion (B7-H3+, PD-L1+, PD-1−) was enriched in AB and B2 thymomas. B7-H3 was overexpressed across all subtypes, with highest expression in high-grade tumours, supporting its candidacy as a therapeutic target.Retrospective variant analysis identified TP53 DNA-binding domain variants (p.C176F and p.E286K), in two thymic carcinomas, with the latter co-occurring with a CDKN2A truncation (p.W110*). A separate metastatic thymoma harboured an NRAS p.Q61R mutation.OncoDEEP profiling confirmed low tumour mutational burden (1.1–4.4 Mut/Mb), microsatellite stability, and absence of homologous recombination deficiency in all cases. Detected variants included NRAS p.Gly13Arg, a canonical MAPK-activating hotspot in a type A thymoma.. Two truncating KMT2C variants were detected in one AB thymoma, implicating epigenetic dysregulation as a mechanism of immune exclusion. Copy number analysis of a type A thymoma revealed gains in 1q and 6p, along with losses in 2q, 3p, 6q, 12p, and 22q, regions harbouring known tumour suppressor genes. These alterations may indicate early genomic instability despite histological classification.Conclusion By mapping immune checkpoint profiles onto genomic alterations and histological subtypes, we reinforce the value of integrated immune-genomic subtyping in this rare malignancy. While limited by cohort size, these findings provide a rationale for biomarker-driven classification and therapeutic stratification in TETs.",
  "authors": [
    {
      "affiliations": [
        "Guys and St Thomas, London, UK",
        "University of Manchester, London, UK",
        "Synnovis, London, UK",
        "Kings College London, London, UK"
      ],
      "name": "R Bensabai"
    },
    {
      "affiliations": [
        "Guys and St Thomas, London, UK",
        "Synnovis, London, UK",
        "Kings College London, London, UK"
      ],
      "name": "G Gerrard"
    },
    {
      "affiliations": [
        "Guys and St Thomas, London, UK",
        "Kings College London, London, UK"
      ],
      "name": "S Gennatas"
    }
  ],
  "title": "S64 Integrative immune and genomic profiling of thymic epithelial tumours: a translational study of biomarkers and therapeutic potential",
  "uid": "e3d0d928-ea7a-5beb-9788-b642415f0ab5"
}