Distinct genomic identities and transformation trajectories of thymomas

Thymoma is a rare tumor originating from epithelial cells of thymus. Despite previous studies, molecular trajectories underlying thymic tumorigenesis remain largely unknown. In this study, we conducted an integrated analysis of genomes and transcriptomes from 124 thymomas and 13 thymic carcinomas. Additionally, we incorporated single-cell transcriptomes of normal thymic tissues collected at different developmental stages. The efforts identify two mutually exclusive molecular types of thymomas: GTF2I-mutant (GTF2I-type) and copy number-altered type (CN-type). The GTF2I-type has a stable copy number profile with cellular identities of transcription similar to thymic progenitor cells. In contrast, CN-type tumors show cellular identities resembling differentiated thymic epithelium with distinct metabolic and immune features and activation of oncogene IRS4. Genome-wide timing analyses on CN-type reveal that tumorigenic courses of the two types were partitioned from the early stage in the lifetime. Our findings provide deep insights into the origin and tumorigenic processes of thymic epithelial cells. Overall design: We produced single-cell RNA-seq data from 11-week-old mice (FVB). Thymi of seven mice were dissected to generate the dataset. Leukocytes were stained with CD45 antibody and depleted with autoMACS Pro Separator. The single-cell RNA sequencing library was generated using Chromium Single Cell 3' Library & Gel Bead Kit v2 (10x Genomics).