Somatic Mutations of Thymic Epithelial Tumors Identified in the Prospective THYMOGENE Trial.

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.