Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

PURPOSE. To reconcile the heterogeneity of thymic epithelial tumors (TETs) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors. <p>EXPERIMENTAL DESIGN. Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.</p> <p>RESULTS. Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild type tumors and represented TETs enriched in expression of genes associated with T cell signaling (TS group; 33%). The remaining 2 groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup.</p> <p>CONCLUSIONS. Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging, and in discovery and development of rational treatment options for patients with TETs.

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