Longitudinal genomic analysis of five cases of recurrent thymomas.

BACKGROUND: Genomic landscape of primary thymic epithelial tumors has been explored previously. However, the molecular alterations contributing to recurrence and potential transformation remain largely unknown.

METHODS: We performed whole-exome sequencing on three primary and eleven recurrent thymoma samples from five patients using the novel EXaCT-2 platform. Genomic alterations, including somatic mutations and copy number variations, were analyzed to investigate clonal evolution and molecular changes during disease progression.

RESULTS: Relapsed tumors exhibited a higher tumor mutational burden than primary tumors. Shared mutations across primary and recurrent samples support a clonal relationship, while distinct alterations in later recurrences suggest ongoing tumor evolution. A total of 313 altered genes were identified across multiple samples in this cohort. Analysis of the TCGA cohort revealed that 11 of these genes exhibited alteration frequencies at least 2.5-fold higher in the progressed group compared to the disease-free group. Histological transformation from type AB to B2/B3 thymoma was observed during the second recurrence in one case. Genes mutated in the transformed sample were altered more frequently in aggressive histological subtypes in the TCGA cohort. The driver mutation GTF2I L424H was detected in relapsed thymomas and was inversely correlated with chromosome 1 amplification/gain.

CONCLUSIONS: Our findings suggest a clonal evolution model in recurrent thymomas, with accumulation of genetic alterations and, in some cases, histological progression. Longitudinal genomic analysis revealed clonal mutations which may inform risk stratification and identify potential therapeutic targets in recurrent TETs.