GTF2I p.L424H is overall the most commonly implicated genetic alteration in thymomas. It is primarily seen in WHO types A and AB and happens to be associated with a favorable prognosis. HRAS mutations also show a strong association with types A and AB, while NRAS and TP53 mutations are more commonly seen in types B2, B3, and thymic carcinoma. Interestingly, the genomic profile of primary versus metastatic thymomas has been shown to be different, with alterations in TP53 being the most common in metastatic thymomas. The same can be said about primary versus metastatic thymic carcinomas. In general, primary lesions seem to be associated with alterations in immune- and metabolic-related pathways, while metastatic lesions tend to involve pathways related to DNA repair, EGFR, RAS, PIK3, and mTOR. This is crucial as it makes rebiopsy and sequencing of a metastatic lesion much more important, even if the mutational status of the primary lesion is already known. Additionally, metastatic lesions have a greater likelihood of demonstrating clinically actionable alterations, further highlighting the importance of sampling metastatic lesions.

With respect to our case, discussion at a multidisciplinary tumor board revealed that the mediastinal mass was confirmed to have preceded the lung mass, supportive of metastasis in this clinical context. KDM6A is a gene involved in chromatin remodeling and is mutated frequently in various entities including multiple myeloma, esophageal squamous cell carcinoma, renal cell carcinoma, and glioblastoma, as well as carcinomas of the pancreas, breast, and colon/rectum. Few cases of thymic carcinoma harboring mutations in KDM6A have been reported in the literature. As such, further studies are warranted to better understand the oncogenic mechanisms in these uncommon scenarios.

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