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

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Year: 2011 Volume: 2

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Petrini, I. Meltzer, P. S. Zucali, P. A. Luo, J. Lee, C. Santoro, A. Lee, H. S. Killian, K. J. Wang, Y. Tsokos, M. Roncalli, M. Steinberg, S. M. Giaccone, G.
Description	Country affiliation: United States Author Affiliation: Petrini I ( Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.)
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 p16(INK4) 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.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.92
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-07-19
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Dna Copy Number Variations Research Support, Non-u.s. Gov't Cell Proliferation Prognosis Aniline Compounds Pyrroles Thymus Neoplasms Transplantation, Heterologous Phenylurea Compounds Autophagy Antagonists & Inhibitors Cyclin-dependent Kinase Inhibitor P15 Cyclin-dependent Kinase Inhibitor P16 Genetics Diagnosis Benzenesulfonates Neoplasms, Glandular And Epithelial Niacinamide Pyridines Tor Serine-threonine Kinases Rna, Small Interfering Pharmacology Metabolism Drug Effects Rna Interference Discipline Cell Biology Pathology Protein Kinase Inhibitors Algorithms Animals Apoptosis Regulatory Proteins Comparative Genomic Hybridization Mice, Nude Sulfonamides Myeloid Cell Leukemia Sequence 1 Protein Cell Line, Tumor Mice Proto-oncogene Proteins C-bcl-2 Analogs & Derivatives Bcl-x Protein
Content Type	Text
Resource Type	Article

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