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

Abstract

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. 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 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. 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.

Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study

“…Thymic carcinoma is known as a 'cold tumour' and has a low tumour mutation burden [18,19]. Previous studies have reported mutations in tumour suppressor genes (TP53, CYLD and CDKN2A), chromatin remodelling genes (BAP1 and PBRM1) and other genes (HRAS and KRAS ) [20], though no targetable mutation or genes associated with costimulatory and coinhibitory T-cell signalling were included [21]. Such genetic information did not strongly support the activity of immune checkpoint inhibitors, while a high PD-L1 expression was still related to a better treatment effect in the pembrolizumab trials.…”

A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma

“…16 Genome analysis has revealed a preponderance of TC (and WHO class B3 thymoma) in a subgroup of thymic malignancies characterized by chromosomal instability (in particular, loss of 16q) and unfavorable survival outcomes. 17 In addition, CD117 (KIT proto-oncogene receptor tyrosine kinase) is frequently overexpressed in TC but not in thymoma. 18,19 These biologic differences may explain the results of our study.…”

Deciphering the biology of thymic epithelial tumors

“…An independent effort at developing a molecular classification of TETs was conducted by Lee and colleagues by using information on DNA mutations, mRNA expression and somatic copy number alterations from the TCGA data set (17). Two independent cohorts from the NCBI Gene Expression Omnibus were used for validation of results.…”