Distinct Associations of GTF2I, TP53, and NOTCH1 Variants with Indolent and Aggressive Thymic Epithelial Tumors in Vietnamese Patients

Background: Thymic epithelial tumors (TETs) are rare neoplasms of the anterior mediastinum, ranging from indolent thymomas to aggressive thymic carcinomas. Increasing evidence suggests that genetic alterations contribute to their pathogenesis and biological behavior. GTF2I, TP53, and NOTCH1 are particularly interesting among the potential genes due to their central roles in transcriptional regulation, cell-cycle control, and oncogenic signaling. Methods: In this study, 150 TET samples from Vietnamese patients were classified according to WHO guidelines and the Masaoka–Koga staging system. Genotyping was conducted on 139 high-quality samples using Sanger sequencing targeting exon 15 of GTF2I, exon 7 of TP53, and exon 34 of NOTCH1. The potential impact of these variants was predicted using the in silico MutationTaster2025 and CADD v1.7 tools. Statistical analyses were also conducted to assess associations between variants and tumor subtypes. Results: Our study identified a total of 17 variants across GTF2I, TP53, and NOTCH1, in which the c.1271T>A variant in the GTF2I hotspot, predicted to be deleterious, was identified in 14.1% of indolent thymomas and showed a significant association with this subtype group (odds ratio: 0.048, adjusted p-value = 0.014). In contrast, previously unreported variants in TP53 (c.772G>A) and NOTCH1 (c.7546T>G) were also computationally predicted to be deleterious and were significantly enriched in aggressive subtypes, with ORs of 15.1 (adjusted p-value = 0.01) and 18.4 (adjusted p-value = 0.026), respectively. Conclusion: These hypothesis-generating findings suggest that variations in GTF2I, TP53, and NOTCH1 may serve as candidate molecular markers for distinguishing thymoma subtypes and assessing patient risk. To date, this is the first targeted hotspot screening study of GTF2I, TP53, and NOTCH1 variants in TETs within the Vietnamese population.