Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma

Timothy Charles Greiner, Chiranjib Dasgupta, Vincent V. Ho, Dennis D. Weisenburger, Lynette M Smith, James C. Lynch, Julie Marie Vose, Kai Fu, James Olen Armitage, Rita M. Braziel, Elias Campo, Jan Delabie, Randy D. Gascoyne, Elaine S. Jaffe, Hans K. Muller-Hermelink, German Ott, Andreas Rosenwald, Louis M. Staudt, Michael Y. Im, Mazen W. KaramanBrian L. Pike, Wing C. Chan, Joseph G. Hacia

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Although mantle cell lymphoma (MCL) frequently harbors inactivated a 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.

Original languageEnglish (US)
Pages (from-to)2352-2357
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number7
DOIs
StatePublished - Feb 14 2006

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Mantle-Cell Lymphoma
Ataxia Telangiectasia
Sequence Deletion
Transcriptome
Alleles
Survival
Genes
Phenotype
Cyclin D1
Gene Deletion
Point Mutation
Cell Cycle
Chromosomes
Genotype
Apoptosis

Keywords

  • Cancer
  • Cell cycle
  • Genetics
  • Microarray
  • Signature

ASJC Scopus subject areas

  • General

Cite this

Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. / Greiner, Timothy Charles; Dasgupta, Chiranjib; Ho, Vincent V.; Weisenburger, Dennis D.; Smith, Lynette M; Lynch, James C.; Vose, Julie Marie; Fu, Kai; Armitage, James Olen; 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 7, 14.02.2006, p. 2352-2357.

Research output: Contribution to journalArticle

Greiner, TC, Dasgupta, C, Ho, VV, Weisenburger, DD, Smith, LM, Lynch, JC, Vose, JM, Fu, K, Armitage, JO, Braziel, RM, Campo, E, Delabie, J, Gascoyne, RD, Jaffe, ES, Muller-Hermelink, HK, Ott, G, Rosenwald, A, Staudt, LM, Im, MY, Karaman, MW, Pike, BL, Chan, WC & Hacia, JG 2006, 'Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 7, pp. 2352-2357. https://doi.org/10.1073/pnas.0510441103
Greiner, Timothy Charles ; Dasgupta, Chiranjib ; Ho, Vincent V. ; Weisenburger, Dennis D. ; Smith, Lynette M ; Lynch, James C. ; Vose, Julie Marie ; Fu, Kai ; Armitage, James Olen ; 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. / Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 7. pp. 2352-2357.
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T1 - Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma

AU - Greiner, Timothy Charles

AU - Dasgupta, Chiranjib

AU - Ho, Vincent V.

AU - Weisenburger, Dennis D.

AU - Smith, Lynette M

AU - Lynch, James C.

AU - Vose, Julie Marie

AU - Fu, Kai

AU - Armitage, James Olen

AU - Braziel, Rita M.

AU - Campo, Elias

AU - Delabie, Jan

AU - Gascoyne, Randy D.

AU - Jaffe, Elaine S.

AU - Muller-Hermelink, Hans K.

AU - Ott, German

AU - Rosenwald, Andreas

AU - Staudt, Louis M.

AU - Im, Michael Y.

AU - Karaman, Mazen W.

AU - Pike, Brian L.

AU - Chan, Wing C.

AU - Hacia, Joseph G.

PY - 2006/2/14

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N2 - Although mantle cell lymphoma (MCL) frequently harbors inactivated a 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.

AB - Although mantle cell lymphoma (MCL) frequently harbors inactivated a 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.

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KW - Cell cycle

KW - Genetics

KW - Microarray

KW - Signature

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