Single-cell analysis of loss of heterozygosity at the ATM gene locus in Hodgkin and Reed-Sternberg cells of Hodgkin's lymphoma: ATM loss of heterozygosity is a rare event

Authors

  • Virginie Lespinet,

    1. INSERM U563, CPTP, Oncogenèse et Signalisation dans les Cellules Hématopoïétiques et Plateau Technique d'Histopathologie Experimentale, IFR30, Purpan Hospital, Toulouse, France
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  • Fanny Terraz,

    1. INSERM U563, CPTP, Oncogenèse et Signalisation dans les Cellules Hématopoïétiques et Plateau Technique d'Histopathologie Experimentale, IFR30, Purpan Hospital, Toulouse, France
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  • Christian Recher,

    1. Department of Hematology, Purpan Hospital, Toulouse, France
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  • Elias Campo,

    1. Department of Anatomic Pathology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
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  • Janet Hall,

    1. DNA Repair Team, International Agency for Research on Cancer, Lyon, France
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  • Georges Delsol,

    1. INSERM U563, CPTP, Oncogenèse et Signalisation dans les Cellules Hématopoïétiques et Plateau Technique d'Histopathologie Experimentale, IFR30, Purpan Hospital, Toulouse, France
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  • Talal Al Saati

    Corresponding author
    1. INSERM U563, CPTP, Oncogenèse et Signalisation dans les Cellules Hématopoïétiques et Plateau Technique d'Histopathologie Experimentale, IFR30, Purpan Hospital, Toulouse, France
    • INSERM U563, CPTP, Oncogenèse et Signalisation dans les Cellules Hématopoïétiques, Hôpital Purpan, Avenue de Grande Bretagne, 31059 Toulouse Cedex 03, France
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    • Fax: +33-5-61-77-94-01


Abstract

Hodgkin's lymphoma (HL) is a lymphoid malignancy characterized by the presence of rare neoplastic cells, Hodgkin and Reed-Sternberg (HRS) cells, scattered among a predominant population of inflammatory cells. On the basis of previously reported cytogenetic analyses, the ATM (ataxia-telangiectasia mutated) gene at 11q22-23 has been implicated in the etiology of HL. We therefore developed a single-cell PCR approach to detect ATM loss of heterozygosity (LOH) in HRS cells. Three microsatellites were investigated; 1 localized inside the ATM gene and the remaining 2 in close proximity. In 2 of the 15 lymph node samples, an allelic loss of the ATM gene locus was detected. ATM protein expression was examined in 8 cases (including 1 of the 2 cases with LOH) by immunohistochemistry. In the case associated with an allelic loss, the ATM protein was absent in the HRS cells, whereas in the 7 remaining cases, without detectable LOH at the ATM locus, nuclear ATM expression was observed. In the 2 HL cases with LOH, the ATM gene was sequenced following whole genome amplification of DNA isolated from microdissected HRS cells. In 1 of these 2 cases, a splice site mutation in the second ATM allele was found. This mutation could generate a premature termination codon leading to a marked instability and a rapid degradation of the resulting ATM mRNA transcripts. This latter event could explain the loss of the expression of the ATM protein in HRS cells as detected by immunohistochemistry in this particular case. As previously reported in some B-cell lymphomas, our results suggest that ATM genetic anomalies could play a role in the pathogenesis of a subset of HL cases. © 2004 Wiley-Liss, Inc.

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