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Thorac Cancer. 2025 Dec;16(24):e70205. doi: 10.1111/1759-7714.70205.

ABSTRACT

BACKGROUND: The molecular landscape of thymic epithelial tumors has been partially elucidated. GTF2I mutation drives the pathogenesis in approximately 50% of tumors; however, the key molecular aberrations in the other cases remain unclear.

METHODS: We designed a panel including the most frequently mutated genes in thymic epithelial tumors and sequenced tumor and normal DNA from 70 patients prospectively accrued at a single institution in the Thymogene trial. Moreover, 19 neoplastic samples were dissociated to isolate tumor cells using flow cytometry.

RESULTS: GTF2I mutations were the most common, being present in 41% of patients. GTF2I mutations were prevalent in type A and AB thymomas, in Stage I-II tumors, and in patients without myasthenia gravis. The unique pattern of mutually exclusive and co-occurring mutations suggests a distinct pathogenesis for thymomas with and without GTF2I mutation. In 39% of patients, no mutations were found in the 77 genes evaluated. The absence of epithelial cells in some dissociated tumors highlights the challenge of identifying mutations in a subset of thymic epithelial tumors that lack the GTF2I mutation. Mutational signatures, including COSMIC 1, 19, and 25, were enriched, possibly linked to 5'-methylcytosine deamination and the effects of chemotherapy.

CONCLUSIONS: GTF2I mutations drive the growth of a significant portion of thymic epithelial tumors, often in conjunction with other gene mutations. Somatic mutations are not commonly found in many GTF2I wild-type tumors, where the underlying genomic abnormalities remain elusive, even when using a dedicated tool for sequencing thymic epithelial tumors.

PMID:41405018 | DOI:10.1111/1759-7714.70205


Source: https://pubmed.ncbi.nlm.nih.gov/4140501 ... 22+67771e2