Context.-The ataxia-telangiectasia mutated (ATM) gene encodes a nuclear 370-kd phosphoprotein known to be associated with chromosomal regions containing doublestrand breaks. The mutations in the ATM gene may be involved in the development of some subtypes of sporadic lymphomas and leukemias. In primary central nervous system diffuse large B-cell lymphomas (PCNS DLBCLs), the pathogenetic role of ATM mutation has not been investigated.

Objective.-To investigate ATM protein expression in PCNS DLBCLs, in comparison with that in non-central nervous system (non-CNS) DLBCLs and to study the relationship of ATM protein loss with several clinicopathologic parameters.

Design.-This study included 42 cases of PCNS DLBCL and 33 cases of non-CNS DLBCL from immunocompetent patients. The ATM protein loss was analyzed by immunohistochemical staining. For the subclassification of DLBCL and analysis of the relationship between ATM and other prognostic markers, we performed immunohistochemical evaluation to detect the following markers: Bcl-6, CD10, multiple myeloma-1, CD138, Bcl-2, Ki-67, and p53.

Results.-The loss of ATM expression was statistically more frequent in PCNS DLBCLs (21/42 cases [50.0%]) than in non-CNS DLBCLs (0/33 cases [0.0%]; P

Conclusions.-Our results suggest that the ATM protein is more strongly correlated with PCNS DLBCL lymphomagenesis than with non-CNS DLBCLs, especially in germinal center B-cell-like subtypes demonstrating low Ki-67 labeling indexes and low Bcl-2 expression.

By definition, primary central nervous system (PCNS) lymphomas are extranodal malignant lymphomas that arise in the parenchyma of CNS in the absence of obvious lymphoma outside the nervous system at the time of the diagnosis.1 Approximately 98% of PCNS lymphomas are B-cell lymphomas.1 In addition, most of these Bcell lymphomas are diffuse large B-cell lymphomas (DLBCLs).2 There is a close association between the Epstein-Barr virus and the PCNS DLBCLs in immunocompromised patients.1 In contrast, no definite etiologic factors have been identified for PCNS DLBCLs in immunocompetent patients.1

The ataxia-telangiectasia mutated (ATM) gene is located on the 11q22 and 11q23 bands and encodes a nuclear 370-kd phosphoprotein associated with chromosomal regions containing double-strand breaks.3 The ATM amino acid sequence contains leucine zipper, helix-turn-helix, and phosphatidylinositol-3 kinase motifs. These features are homologous to those of diverse protein kinases involved in checkpoint/damage responses, such as Tel1p, ATR, Rad3, Nec1p, Mei-41, and DNA-PKcs.3 The ATM acts as an upstream mediator of a kinase cascade that links DNA damage detection to cell-cycle progression, genetic recombination, and apoptosis.4,5 Germline mutations in the ATM gene are the cause of ataxia-telangiectasia, an autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, hypersensitivity to ionizing radiation, immunodeficiency, chromosomal instability, and cancer susceptibility.6 Several studies have indicated that missense and loss-of-function mutations in the ATM gene may also be involved in the development of some subtype of sporadic lymphomas and leukemias including T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell chronic lymphocytic leukemia.3,7 Several lines of evidence suggest that alterations of ATM in lymphoid neoplasia are not confined to mantle cell lymphoma, T-cell prolymphocytic leukemia, and B-cell chronic lymphocytic leukemia but may be involved in a broader range of histologic subtypes such as DLBCL, follicular lymphoma, and adult acute lymphoblastic leukemia.3,7 The ATM alterations with a putative pathogenetic effect have been found in approximately 13% to 20% of DLBCL cases. 7,8 In PCNS DLBCL, the pathogenic role of ATM mutation has not been investigated.

As with non-CNS DLBCLs,9 PCNS DLBCLs can be subclassified into the germinal center B-cell-like (GCB) or activated B-cell-like (ABC) subtype based on their immunoexpression of CD10 and Bcl-6.10 A study demonstrated that the GCB subtype (CD10^sup +^ or Bcl-6^sup +^) of non-CNS DCLBL had a better prognosis than the ABC subtype (CD10- and Bcl-6-).9 Since then, several studies have tried to document the effects of Bcl-6 immunoreactivity of PCNS DLBCL on survival.11-13 However, the results are still controversial. According to one study, PCNS DLBCLs may show a poorer prognosis than non-CNS DLBCLs.13 Camilleri-Broët et al2 explained that the poor prognosis of PCNS DLBCLs might be attributed to the “activated B celllike pattern,” which is not prevalent in non-CNS DLBCLs.

Until this time, most ATM mutation studies in DLBCL were performed using molecular genetic tools.7,8 Recently, retrospective studies on the expression of ATM by immunohistochemical staining were made possible because of the development of the antibodies that work on routinely processed tissue sections. Because of this development, a few retrospective studies on ATM immunohistochemical expression in breast, prostate, and colorectum have been completed.14-20 The results of these studies supported the validity and clinical usefulness of an immunohistochemical analysis of the ATM protein as the final product of gene alterations.15-17,19 In our study, we evaluated the ATM expression in PCNS DLBCLs in comparison with ATM expression in non-CNS DLBCLs and correlated ATM expression status with histogenetic PCNS DLBCL subclassification, survival, and other parameters.