Primary Driver Mutations in GTF2I Specific to the Development of Thymomas

Abstract

Thymomas are rare mediastinal tumors that are difficult to treat and pose a major public health concern. Identifying mutations in target genes is vital for the development of novel therapeutic strategies. Type A thymomas possess a missense mutation in <i>GTF2I</i> (chromosome 7 c.74146970T>A) with high frequency. However, the molecular pathways underlying the tumorigenesis of other thymomas remain to be elucidated. We aimed to detect this missense mutation in <i>GTF2I</i> in other thymoma subtypes (types B). This study involved 22 patients who underwent surgery for thymomas between January 2014 and August 2019. We isolated tumor cells from formalin-fixed paraffin-embedded tissues from the primary lesions using laser-capture microdissection. Subsequently, we performed targeted sequencing to detect mutant <i>GTF2I</i> coupled with molecular barcoding. We used PyClone analysis to determine the fraction of tumor cells harboring mutant <i>GTF2I</i>. We detected the missense mutation (chromosome 7 c.74146970T>A) in <i>GTF2I</i> in 14 thymomas among the 22 samples (64%). This mutation was harbored in many type B thymomas as well as type A and AB thymomas. The allele fraction for the tumors containing the mutations was variable, primarily owing to the coexistence of normal lymphocytes in the tumors, especially in type B thymomas. PyClone analysis revealed a high cellular prevalence of mutant <i>GTF2I</i> in tumor cells. Mutant <i>GTF2I</i> was not detected in other carcinomas (lung, gastric, colorectal, or hepatocellular carcinoma) or lymphomas. In conclusion, the majority of thymomas harbor mutations in <i>GTF2I</i> that can be potentially used as a novel therapeutic target in patients with thymomas.