Copy number aberrations of BCL2 and CDKN2A/B identified by array-CGH in thymic epithelial tumors

I Petrini,Y Wang,G Giaccone,K J Killian,S M Steinberg,C Lee,P A Zucali,H S Lee,M Roncalli,A Santoro,P S Meltzer,J Luo,M Tsokos

doi:10.1038/cddis.2012.92

Abstract

The molecular pathology of thymic epithelial tumors (TETs) is largely unknown. Using array comparative genomic hybridization (CGH), we evaluated 59 TETs and identified recurrent patterns of copy number (CN) aberrations in different histotypes. GISTIC algorithm revealed the presence of 126 significant peaks of CN aberration, which included 13 cancer-related genes. Among these peaks, CN gain of BCL2 and CN loss of CDKN2A/B were the only genes in the respective regions of CN aberration and were associated with poor outcome. TET cell lines were sensitive to siRNA knockdown of the anti-apoptotic molecules BCL2 and MCL1. Gx15-070, a pan-BCL2 inhibitor, induced autophagy-dependent necroptosis in TET cells via a mechanism involving mTOR pathways, and inhibited TET xenograft growth. ABT263, an inhibitor of BCL2/BCL-XL/BCL-W, reduced proliferation in TET cells when administered in combination with sorafenib, a tyrosine kinase inhibitor able to downregulate MCL1. Immunohistochemistry on 132 TETs demonstrated that CN loss of CDKN2A correlated with lack of expression of its related protein p16INK4 and identified tumors with poor prognosis. The molecular markers BCL2 and CDKN2A may be of potential value in diagnosis and prognosis of TETs. Our study provides the first preclinical evidence that deregulated anti-apoptotic BCL2 family proteins may represent suitable targets for TET treatment.

Highlights

The length of each copy number (CN) aberration was expressed as the percentage of a relative chromosome arm, and CN aberrations were divided into 10 groups according to the proportion of the chromosome affected (Figure 1a)
The number of CN aberrations progressively decreased in inverse proportion to their length up to 80% of their respective chromosome arms, and rose again reaching a second peak at 90–100%
We studied the genomic CN aberrations of thymic epithelial tumors (TET) to identify potential prognostic factors and targets suitable for therapy

Summary

Introduction

Chromosome arm-level CN loss of 13q occurs in more aggressive TETs. In univariate analyses, loss of 13q was associated with a poorer time to progression (TTP; log-rank test, P 1⁄4 0.013; Figure 1c) and disease-related survival (DRS; P 1⁄4 0.065; Figure 1d). To identify the potential importance of CN aberrations in the biology of TETs, we applied the GISTIC algorithm[5] to TET CGH data and identified 72 peaks of CN gain (817 genes þ 23 miRNAs) and 54 of CN loss (155 genes þ 3 miRNAs) (Figures 2a and b, Supplementary Table S3).

Results

Conclusion