A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas

Abstract

Background:Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing.Methods:The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used.Results:Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability.Conclusions:A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855).

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

“…Today, there is growing evidence that these thymic malignancies represent histologically and molecularly distinct neoplasms. [13][14][15] Compared with thymoma, TC is more aggressive and more likely to metastasize outside the chest cavity. 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.…”

Deciphering the biology of thymic epithelial tumors

“…Radovich and colleagues analyzed 13 TET samples and found overexpression of a large miRNA cluster on chromosome 19q13.42 (C19MC) in type A and AB thymomas resulting in activation of the PI3K/AKT pathway (33). In contrast, C19MC expression was absent in type B thymomas.…”

The Integrated Genomic Landscape of Thymic Epithelial Tumors

“…Exome sequencing has revealed a high frequency of recurrent mutations in the GTF2I gene in type A and AB thymomas (Petrini et al, 2014). More recent data have demonstrated overexpression of a large microRNA cluster on chromosome 19 in type A and AB thymomas, which is associated with PI3K/AKT activation (Radovich et al, 2016). There have been few attempts at more comprehensive molecular analyses of TETs and these studies have utilized a limited number of molecular platforms (Ganci et al, 2014; Huang et al, 2013; Lopez-Chavez et al, 2015; Petrini et al, 2013; Wang et al, 2014).…”