Integrative Multiomic Classification Reveals Distinct Origins and Evolutionary Trajectories of Thymic Epithelial...

Area of Science:

• Oncology
• Genomics
• Transcriptomics

Background:

• Thymic epithelial tumors (TETs) include thymomas and thymic carcinomas, originating from thymic epithelial cells (TECs).
• Histologic subtypes of TETs exhibit diverse immune cell compositions and clinical features.
• Understanding TET heterogeneity is crucial for improved patient stratification and treatment.

Purpose of the Study:

• To investigate the cellular origins and molecular pathways driving TET heterogeneity.
• To stratify TETs into distinct subgroups using integrated genomic and transcriptomic data.
• To identify potential cells of origin for different TET subtypes.

Main Methods:

• Integrated genomic and transcriptomic analysis of 137 TET cases (124 thymomas, 13 thymic carcinomas).
• Incorporation of single-cell transcriptomic data from murine thymic tissues.
• Bioinformatic analysis to stratify tumors and compare transcriptional profiles.

Main Results:

• TETs stratified into three subgroups: GTF2I-mutant (GTF2I-type) thymomas, copy number-altered (CN-type) thymomas, and thymic carcinomas.
• GTF2I-type thymomas resemble thymic epithelial progenitors (TEPs).
• CN-type thymomas exhibit similarities to differentiated TECs, with early copy-number alterations.
• Thymic carcinomas show profiles comparable to thymic tuft cells, with high mutational burdens.
• Subgroups differ in transcriptional programs, including lipid metabolism and immune phenotypes.

Conclusions:

• Integrated genomics reveals distinct cellular origins and evolutionary paths for TET subgroups.
• Findings provide insights into the tumorigenic processes of thymomas and thymic carcinomas.
• This classification approach enhances understanding of TET heterogeneity and supports personalized medicine.