Absence of ATM hypermethylation in mantle cell and follicular lymphoma

Abstract

patients are required to define the true efficacy of 153 Sm-EDTMP in eradicating MM, based on our experience, we believe that the agent should not be used as a substitute for TBI in preparative regimens in either autologous or allogeneic SCT. As such, we find the 'augmented' approach by Dispenzieri et al 1 very promising, and await with interest the results of their phase 2 trial. Mantle cell lymphoma (MCL) and follicular lymphoma (FL) are two forms of B-cell lymphoma derived from neoplastic transformation of their normal counterparts in the mantle zone and germinal center, respectively. 1 MCL is characterized in virtually all cases by t(11;14), with dysregulation of the cell cycle by upregulation of cyclin D1 located at 11q13. 1 On the other hand, FL is characterized by t(14;18) and upregulation of BCL-2 located at 18q21, which confers resistance to apoptosis on the malignant lymphoid cells. 1 ATM (A-T mutated) gene (localized to chromosome 11q22.3) encodes a cell cycle checkpoint-specific, serine-threonine kinase. In response to double-stranded DNA breaks (DSBs), ATM phosphorylates a panel of proteins including p53, Chk1, BRCA1 and Nbs1, resulting in cell cycle arrest and DNA repair, and is thus important in maintaining the integrity of the genome. This ensures passage of an intact genome in dividing cells, and elimination of cells carrying nonrepairable DSBs. 2 Mutation of ATM leads to ataxia telangiectasia, an autosomal recessive disorder, which is characterized by neurodegeneration, immunodeficiency and increased risk of cancer including lymphomas.In addition to the upregulation of cylin D1 associated with t(11;14) in MCL, a commonly deleted region at 11q22-q23 that encompasses the ATM locus has been identified in MCL. Subsequent mutation analysis of ATM, in 12 sporadic cases of MCL, showed a deletion of one ATM gene copy in seven, all of which harbored an inactivating point mutation in the remaining allele. In addition, biallelic ATM mutations were identified in two MCL patients without 11q deletions. 3 Using a microarray to screen lymphomas from 120 patients (including 28 MCL and 18 FL) for all possible ATM coding and splice junction mutations, ATM mutations were shown to be most frequent (12/28; 43%) in the mantle cell (MCL) subtype, but absent in FL. 4 In addition to deletion and mutation, methylation of gene promoter sites has now been identified as a frequently encountered mechanism of gene silencing in tumors. Indeed, ATM is frequently methylated in breast cancer. 5 Catalyzed by DNA methyltransferase, DNA methylation involves the addition of a methyl group to the carbon 5 position of the cytosine ring in the CpG dinucleotide, to form methylcytosine. 6 In many cancers, the CpG islands of selected genes are aberrantly methylated (hypermethylated), resulting in the repression of transcription of these genes. 6 Methylation, thus, can serve as an alternative Kaplan-Meier estimates of PFS, 153 Sm-EDTMP-based vs Cy-TBI preparative regimens.

Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle cell lymphomas

“…42 So far, there is only one study about epigenetic mechanisms leading to the inactivation of ATM in MCL showing the absence of ATM hypermethylation in eight primary cases as well as in Granta-519 cells. 43 The discrepancy between these and our results may be explained by the fact that although the identical promoter region was analyzed (position -4578 to -4799 on the genomic level based on the ATM transcription start site), different primers, leading to a larger PCR fragment, were used. Since methylation of a tumor suppressor gene does not mean that each CpG site is methylated and that methylation is 100% at each site, primer design has a big impact on the results.…”

A putative “hepitype” in the ATM gene associated with chronic lymphocytic leukemia risk

“…However, we found no evidence of ATM promoter hypermethylation in any of the analyzed samples. These data corroborate previous studies suggesting that epigenetic silencing of ATM by promoter hypermethylation is a rare event in the majority of lymphomas (Chim et al, 2005;Gumy-Pause et al, 2006;Bose et al, 2007).…”

Analysis of hypermethylation and expression profiles of APC and ATM genes in patients with oral squamous cell carcinoma

“…On the contrary, a study on a full range of B-cell lines with variable degrees of differentiation showed that methylation of ATM gene is far less frequent in lymphomagenesis compared to deletions and mutations [37]. …”