Haematologica 2003; 88:(11) ELT33

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ABSENCE OF ATM DELETIONS IN 16 CASES OF SPLENIC MARGINAL ZONE B-CELL LYMPHOMA
Marta Salido (1,3), Laura Astier (1,2), Eulàlia Puigdecanet (1,2), Blanca Espinet (1,3), Lourdes Florensa (2,3), Francesc Solé (1,3)
(1) Laboratori de Citogenètica i Biologia Molecular. Servei de Patologia. Hospital del Mar-IMAS. Barcelona. Spain; (2) Laboratori de Citologia Hematològica. Servei de Patologia. Hospital del Mar. Barcelona . Spain; (3) Escola de Citologia Hematològica Soledad Woessner-IMAS.
Correspondence: Marta Salido
Laboratori de Citogenètica i Biologia Molecular, Servei de Patologia, Hospital del Mar, Passeig Marítim 25-29, 08003 Barcelona; Spain
Tel. 34-93-248.30.35 Fax. 34-93-248.31.31
ABSTRACT
We present a study of 16 cases of splenic marginal zone B-cell lymphoma (SMZBL) combining conventional cytogenetics and fluorescence in situ hybridization technique (FISH). We used a locus-specific probe (11q22.3) that hybridizes with ataxia telangiectasia mutated (ATM) gene and a centromeric probe of chromosome 11 as a control. Deletions in the ATM gene region have been found in B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) and have been considered as an independent prognostic factor in these pathologies. The aim of our study was to determine the ATM status in SMZBL because no specific studies concerning ATM status in SMZBL have been reported and other B-cell malignances have shown ATM deletions. No deletions were detected in any of the 16 cases. ATM deletions can be considered a rare event in SMZBCL.
Splenic marginal zone B-cell lymphoma (SMZBL) is a specific low grade small B-cell lymphoma with clinical, morphological, immunophenotypic and histologic characteristics well established by the WHO classification. Clinically, patients present with splenomegaly, and bone marrow and peripheral blood are usually affected. Immunophenotypically, tumor cells express surface IgM and IgD and are CD20+, CD79a+, CD5-, CD10-, CD23-, CD43+/- and cyclin D1-. The most frequent cytogenetic aberrations are deletions at 7q22-q321,2 and gains of chromosome 3/3q3. The common area of deletion identified by FISH in chromosome 7 spans from 7q32.1-7q32.32. Gazzo et al.3 delineated the common 3q13.32-3q29 overrepresented region by FISH in 14 cases of marginal zone B-cell lymphomas (MZBCL), 13 of them with splenic origin.

The aim of our study was to define the ataxia telangiectasia mutated (ATM) gene status in SMZBL, which is inactivated in ataxia-telangiectasia disease (A-T). The ATM gene is a tumor suppressor gene located at 11q22.3. The ATM protein is a member of the phophatidylinositol-3 kinase family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and cell cycle control. Different studies indicate an association of 11q22-23 deletions involving the ATM locus and B-cell lymphomagenesis4. Structural aberrations involving 11q are present mainly in B-cell chronic lymphocytic leukemia (B-CLL)5 and mantle cell lymphoma (MCL)6. Deletions at the ATM locus are associated with karyotype complexity and severe outcome in indolent as well as in aggressive lymphomas4,6. Since no specific studies concerning ATM status in SMZBL have been reported and deletions in ATM are involved in B-cell malignancies, we considered it interesting to determine ATM status in SMZBL, combining conventional cytogenetics and FISH techniques.

Cytogenetic and FISH studies were performed in 16 SMZBCL following standard protocols. In our series, the overall incidence of chromosome abnormalities was 8/16 (50%), four of them with a complex karyotype (25%). The most frequently observed chromosome aberration was deletion 7q32 in 6 cases, in three of them as a sole anomaly and in the other three cases in a complex karyotype. Four out of sixteen patients (25%) had chromosome 3 aberrations, three of them as trisomy 3. In one case with a complex karyotype, we observed a del(11)(q21q23) (Table 1).

To detect ATM deletions, we used a Spectrum Orange labeled locus specific ATM probe (VYSIS, Inc Downers Grove, IL) and a Spectrum Green labeled chromosome 11 centromere probe (VYSIS, Inc Downers Grove, IL). FISH was scored considering a deletion when at least more than 5% of nuclei presented only one signal of ATM showing both 11 centromeric signals. Considering this cut-off, no patients out of 16 carried the ATM deletions (Table 1). It is interesting to note that one patient presented 11q21q23 deletion by cytogenetics; however, when FISH with ATM was applied, no ATM deletion was detected (Figure 1).

Our results are in concordance with the findings of Hernandez et al.7 using comparative genomic hybridization (CGH) in 29 SMZBL patients in whom no representative 11q losses were described.

In the series of Cuneo et al.4 53 indolent and 82 agressive lymphomas were studied by conventional cytogenetic analysis and by FISH using an 11q22-23 probe that recognizes ATM sequences. Fifteen of 135 cases (11%) had ATM deletion; four patients had an indolent lymphoma (follicular center cell lymphoma), and eleven patients showed an aggressive lymphoma (five mantle-cell lymphomas and six diffuse large-cell lymphomas). In an additional series of Cuneo et al.8 9 out of 14 MZBCL studied by FISH with the ATM locus were of splenic origin and only one of them had ATM deletion.

Reviewing large cytogenetic series of SMZBCL (Oscier et al9, Troussard et al10 and Sole et al1) we found only 3/122 patients with a deletion at 11q. Our results and those reviewed in the literature suggest that ATM deletion is not involved in the pathogenesis of SMZBL and is a rare cytogenetic event. Due to the small size of our series and the existence of reports demonstrating ATM mutations in other types of lymphomas, we consider that additional studies are needed to determine the clinical implications of ATM deletions in SMZBL.

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