Abstract
Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lymphocytes with 5-year overall survival rates of only ∼ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogenesis of PTCL, with a resulting paucity of molecular targets for therapy. We developed bioinformatic tools to identify chromosomal rearrangements using genome-wide, next-generation sequencing analysis of mate-pair DNA libraries and applied these tools to 16 PTCL patient tissue samples and 6 PTCL cell lines. Thirteen recurrent abnormalities were identified, of which 5 involved p53-related genes (TP53, TP63, CDKN2A, WWOX, and ANKRD11). Among these abnormalities were novel TP63 rearrangements encoding fusion proteins homologous to ΔNp63, a dominant-negative p63 isoform that inhibits the p53 pathway. TP63 rearrangements were seen in 11 (5.8%) of 190 PTCLs and were associated with inferior overall survival; they also were detected in 2 (1.2%) of 164 diffuse large B-cell lymphomas. As TP53 mutations are rare in PTCL compared with other malignancies, our findings suggest that a constellation of alternate genetic abnormalities may contribute to disruption of p53-associated tumor suppressor function in PTCL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p16 / chemistry
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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 Mutational Analysis
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Female
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Gene Rearrangement*
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Genome-Wide Association Study
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Humans
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Lymphoma, Large B-Cell, Diffuse / genetics
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Lymphoma, Large B-Cell, Diffuse / mortality
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Lymphoma, Large B-Cell, Diffuse / pathology
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Lymphoma, T-Cell, Peripheral / genetics*
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Lymphoma, T-Cell, Peripheral / metabolism
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Lymphoma, T-Cell, Peripheral / mortality
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Lymphoma, T-Cell, Peripheral / pathology
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Male
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Mutation*
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / chemistry
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Oxidoreductases / chemistry
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Oxidoreductases / genetics
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Oxidoreductases / metabolism
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Repressor Proteins / chemistry
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Sequence Homology, Nucleic Acid
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Transcription Factors / chemistry
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
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United States
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WW Domain-Containing Oxidoreductase
Substances
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ANKRD11 protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Mutant Proteins
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Oncogene Proteins, Fusion
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Repressor Proteins
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TP53 protein, human
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TP63 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Oxidoreductases
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WW Domain-Containing Oxidoreductase
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WWOX protein, human