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

Clin Cancer Res. 2017 Aug 15;23(16):4855-4864. doi: 10.1158/1078-0432.CCR-17-0066. Epub 2017 Apr 11.


Purpose: To reconcile the heterogeneity of thymic epithelial tumors (TET) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors.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.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 two 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.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 the discovery and development of rational treatment options for patients with TETs. Clin Cancer Res; 23(16); 4855-64. ©2017 AACR.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • DNA Copy Number Variations
  • Disease-Free Survival
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic*
  • Genomics / methods*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasms, Glandular and Epithelial / classification
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / pathology
  • Thymus Neoplasms / classification
  • Thymus Neoplasms / genetics*
  • Thymus Neoplasms / pathology
  • Young Adult