title: Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma.
abstract: 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 D1-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 ATM 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.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. tgreiner@unmc.edu
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.forename: Vincent V
authors.initials: VV
authors.lastname: Ho
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Smith
authors.forename: James C
authors.initials: JC
authors.lastname: Lynch
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.forename: James O
authors.initials: JO
authors.lastname: Armitage
authors.forename: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Hans K
authors.initials: HK
authors.lastname: Muller-Hermelink
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Im
authors.forename: Mazen W
authors.initials: MW
authors.lastname: Karaman
authors.forename: Brian L
authors.initials: BL
authors.lastname: Pike
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Hacia
mesh_terms: D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality*; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases