The Integrated Genomic Landscape of Thymic Epithelial Tumors

Abstract

Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.

A mutation analysis of the EGFR pathway genes, RAS, EGFR, PIK3CA, AKT1 and BRAF, and TP53 gene in thymic carcinoma and thymoma type A/B3

“…In the previous six studies, the gene mutation frequencies ranged from 10% to 27% and 0% to 5%, respectively . Compared with the previous studies, the TP 53 mutations in thymoma were similarly rare in our series, but those in thymic carcinoma were somewhat less frequent . In two of the previous six reports, TP53 mutations were correlated with a worse prognosis of thymic carcinoma patients .…”

“…In the present study, TP53 mutation was detected in five of 54 (9.3%) and none of 33 (0.0%) cases of thymic carcinoma and thymoma type A/B3, respectively. In the previous six studies, the gene mutation frequencies ranged from 10% to 27% and 0% to 5%, respectively . Compared with the previous studies, the TP 53 mutations in thymoma were similarly rare in our series, but those in thymic carcinoma were somewhat less frequent .…”

“…To our knowledge, there have been a limited number of studies describing the EGFR pathway mutations in thymic carcinoma . One study used conventional Sanger sequencing, and the other six used next‐generation sequencing (NGS) . In these studies, the EGFR pathway as well as RAS family gene mutation rates were less than 12%.…”

“…However, targeted approaches have not been well clarified in thymic epithelial tumours. Recent genetic analyses have shown that TP53 mutations are frequent in thymic carcinomas, suggesting an important oncogenic role of this molecule …”

“…Recent genetic analyses have shown that TP53 mutations are frequent in thymic carcinomas, suggesting an important oncogenic role of this molecule. [17][18][19][20][21][22] In this study, we conducted a genetic analysis of the EGFR pathway and TP53 to gain more insight into the molecular pathogenesis and to detect driver gene mutations in a large cohort of thymic carcinomas, and the results were compared with those of thymoma type A/B3.…”