Mutation and Genomic Deletion Status of ataxia telangiectasia mutated (ATM) and p53 Confer Specific Gene Expression Profiles in Mantle Cell Lymphoma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 7; pp. 2352 - 2357
• Main Authors: Greiner, Timothy C., Dasgupta, Chiranjib, Ho, Vincent V., Weisenburger, Dennis D., Smith, Lynette M., Lynch, James C., Vose, Julie M., Fu, Kai, Armitage, James O., Braziel, Rita M., Campo, Elias, Delabie, Jan, Gascoyne, Randy D., Jaffe, Elaine S., Muller-Hermelink, Hans K., Ott, German, Rosenwald, Andreas, Staudt, Louis M., Im, Michael Y., Karaman, Mazen W., Pike, Brian L., Chan, Wing C., Hacia, Joseph G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14-02-2006; National Acad Sciences
• Subjects: Alleles; Apoptosis - genetics; Ataxia telangiectasia; Ataxia Telangiectasia Mutated Proteins; Biological Sciences; Cell cycle; Cell Cycle - genetics; Cell Cycle Proteins - genetics; Chromosomes; Cyclin D1 - genetics; DNA-Binding Proteins - genetics; Gene expression; Gene Expression Profiling; Genes; Genes, Neoplasm; Genetic loci; Genetic mutation; Genome, Human - genetics; Genomics; Genotype & phenotype; Humans; Lymphoma; Lymphoma, Mantle-Cell - genetics; Lymphoma, Mantle-Cell - mortality; Mutation; Point Mutation; Protein-Serine-Threonine Kinases - genetics; Sequence Deletion; Signatures; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - genetics; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0510441103

Although mantle cell lymphoma (MCL) frequently harbors inactivated ataxia telangiectasia mutated (ATM) and p53 alleles, little is known about the molecular phenotypes caused by these genetic changes. We identified point mutations and genomic deletions in these genes in a series of cyclin Dl-positive MCL cases and correlated genotype with gene expression profiles and overall survival. Mutated and/or deleted ATM and p53 alleles were found in 56% (40/72) and 26% (21/82) of the cases examined, respectively. Although MCL patients with inactive p53 alleles showed a significant reduction in median overall survival, aberrant A TM status did not predict for survival. Nevertheless, specific gene expression signatures indicative of the mutation and genomic deletion status of each gene were identified that were different from wild-type cases. These signatures were comprised of a select group of genes related to apoptosis, stress responses, and cell cycle regulation that are relevant to ATM or p53 function. Importantly, we found the molecular signatures are different between cases with mutations and deletions, because the latter are characterized by loss of genes colocalized in the same chromosome region of ATM or p53. This information on molecular phenotypes may provide new areas of investigation for ATM function or may be exploited by designing specific therapies for MCL cases with p53 aberrations.