Thymic epithelial tumours (TETs) are rare intrathoracic tumours. The key genetic drivers are yet to be discovered. The aim of this research project was to differentiate different TET subsets at the molecular level and identify potential drivers and immunohistochemical targets for each.

Sanger sequencing was used to assess the frequency of the known mutation in GTF2I. The prevalence in our cohort of 141 TETs was 34%, being as high as 90% and 69% in type A and AB thymomas respectively. There were no squamous cell carcinomas (SCCs), neuroendocrine thymic tumours (NETTs) or hyperplasias with the mutation. This is a novel finding that could be of diagnostic value in difficult to diagnose mediastinal masses.

Whole exome sequencing (WES) was performed on seventeen TETs and was analysed with the unpublished 'Cancer Genome Atlas' (TCGA) data. 25% of GTF2I mutant type A and AB thymomas also had an oncogenic mutation affecting the MAP kinase pathway. The most commonly mutated gene in carcinomas was TP53 (30%). A recurrent germline insertion in HLA-A was seen across the TET subtypes at a frequency of 27%.

Single nucleotide polymorphism (SNP) genotyping on 143 TETs identified multiple genes with copy number gains in chromosome 1q. Very few recurrent copy number losses were seen. A notable exception was MUTYH that was shown to have recurrent, homozygous copy number losses in 18% of all TETs and 25% of SCCs.

Eight immunotherapy and two other emerging targets were targeted with immunohistochemistry in 143 TET tissue microarrays. PD-L1, PD-L2 and B7-H3 were the most positive markers. Overall aggressive TETs demonstrated higher staining scores. Clustering of all TETs according to their co-expression of these markers revealed cases in all subtypes that clustered more with other TET subtypes.

These results require validation and expansion. Whole genome sequencing, expression and methylation studies are also needed.