Thymic Epithelial Tumor (TET)

Overview

Thymic epithelial tumors (TETs) encompass a spectrum from indolent thymomas (WHO types A, AB, B1, B2, B3) to aggressive thymic carcinomas; in OncoTree TET is the parent of THYM and THYC under THYMUS. A landmark WES study of 274 TETs (dataset: tet_nci_2014) identified a single recurrent GTF2I hotspot missense mutation (chr7:74146970 T>A, p.Leu404His) as the dominant driver in indolent histotypes, present in 43.4% of all TETs and 78% of type A/AB thymomas but only 8% of thymic carcinomas.

Cohorts in the corpus

  • tet_nci_2014 — 286 patients from NCI, Pisa, Padua, and Humanitas; WES (n=28), targeted 197-gene panel (n=52), aCGH (n=65), RNA-seq (n=25), Sanger GTF2I (n=199); referenced in PMID:24974848.

Recurrent alterations

  • GTF2I chr7:74146970 T>A → p.Leu404His is present in 43.4% (119/270) of TETs overall; 78% of type A/AB thymomas; 8% of thymic carcinomas; correlates with 96% vs 70% 10-year disease-related survival (log-rank P<0.001); mutant TFII-I protein is post-transcriptionally stabilised via RXXL destruction-box disruption PMID:24974848.
  • TP53, CYLD, CDKN2A, BAP1, PBRM1 are recurrently mutated in thymic carcinomas; mean mutation burden 43.5 per sample in carcinomas vs 18.4 in thymomas (Mann-Whitney U P=0.001) PMID:24974848.
  • BCL2 focal amplification (GISTIC peak) correlated with increased BCL2 transcript expression across aggressive TETs PMID:24974848.
  • Arm-level copy-number losses: 6p (26%), 6q (29%), 3p (22%), 13q (18%); gains: 1q (55%), 7p (20%), 7q (15%), 20p (17%); enriched in aggressive histotypes PMID:24974848.
  • BRD4–NUTM1 fusion present in TY82 thymic carcinoma cell line PMID:24974848.

Subtypes

  • WHO type A/AB thymomas: indolent, GTF2I-mutation dominant.
  • WHO type B1/B2/B3 thymomas: intermediate aggressiveness, lower GTF2I prevalence.
  • Thymic carcinoma (THYC): aggressive, TP53/CYLD/CDKN2A/BAP1/PBRM1 mutated, high CNV burden.

Therapeutic landscape

  • KIT mutations in ~10% of thymic carcinomas represent a potential targetable lesion (literature context) PMID:24974848.
  • GTF2I mutation is a growth-promoting but non-transforming oncogene; not directly druggable as characterised.

Sources

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