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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Algorithms
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Aniline Compounds / pharmacology
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Animals
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects
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Benzenesulfonates / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Comparative Genomic Hybridization
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Cyclin-Dependent Kinase Inhibitor p15 / genetics*
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Cyclin-Dependent Kinase Inhibitor p15 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / genetics*
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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DNA Copy Number Variations
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Female
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Humans
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Indoles
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Male
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Mice
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Mice, Nude
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Middle Aged
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasms, Glandular and Epithelial / diagnosis
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Neoplasms, Glandular and Epithelial / metabolism*
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Neoplasms, Glandular and Epithelial / pathology
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Niacinamide / analogs & derivatives
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Phenylurea Compounds
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Prognosis
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridines / pharmacology
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Pyrroles / pharmacology
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RNA Interference
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RNA, Small Interfering
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Sorafenib
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Sulfonamides / pharmacology
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TOR Serine-Threonine Kinases / metabolism
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Thymus Neoplasms / diagnosis
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Thymus Neoplasms / metabolism*
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Thymus Neoplasms / pathology
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Transplantation, Heterologous
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / metabolism
Substances
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Aniline Compounds
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Apoptosis Regulatory Proteins
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BCL2L2 protein, human
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Benzenesulfonates
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Cyclin-Dependent Kinase Inhibitor p15
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Cyclin-Dependent Kinase Inhibitor p16
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Indoles
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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Pyrroles
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RNA, Small Interfering
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Sulfonamides
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bcl-X Protein
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Niacinamide
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Sorafenib
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TOR Serine-Threonine Kinases
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obatoclax
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navitoclax