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

Abstract

Although mantle cell lymphoma (MCL) frequently harbors inactivated 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 and͞or deleted ATM and p53 alleles were found in 56% (40͞72) and 26% (21͞82) 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.cancer ͉ cell cycle ͉ genetics ͉ microarray ͉ signature M antle cell lymphoma (MCL) is an aggressive tumor that accounts for Ϸ6% of all non-Hodgkin lymphoma cases in the U.S., with higher rates in North America (1, 2). Although the median survival of MCL patients is only 3 years, some individuals survive Ͼ10 years from the time of diagnosis (2, 3). There is considerable interest in defining the molecular basis for this clinical heterogeneity to develop better prognostic markers and more effective therapies.MCL corresponds to B cells of the mantle zone of the lymphoid follicles that have acquired distinctive alterations in genes related to cell cycle control and apoptosis (4). The hallmark of these genetic alterations is the t(11;14)(q13;q32) translocation that juxtaposes the IGH locus near the CCND1 gene, resulting in the overexpression of cyclin D1 (5). A subset of MCL cases acquire p53 mutations, and these patients have a significantly shortened median survival relative to cases with wild-type p53 (6-8). Interestingly, the ataxia telangiectasia mutated (ATM) gene, whose product regulates some p53-dependent apoptosis pathways, is mutated or deleted in 25-40% of MCL cases (reviewed in refs. 9 and 10). Although preliminary studies suggest that ATM mutation status does not have a significant impact on patient survival (7, 11), they may have lacked the statistical power to identify more subtle effects on survival, such as the effect of functional subsets of mutations.We determined the ATM and p53 genotypes in a large cohort of MCL cases with previous gene expression profiles to further elucidate the relationship between molecular phe...

Allelic genotyping reveals a hierarchy of genomic alterations in mantle cell lymphoma associated to cell proliferation

“…Accordingly, Tamaru et al concluded that overexpression of p53 and p27KIP1 may be linked to a cellular mechanism involved in the development of the variant form of MCL [47]. Mutant p53 alleles were also correlated to proliferation signature and worse overall survival in comparison to wild-type cases [20]. In line with these observations, LOH in 17p13.1 harboring p53 were associated to members of the proliferation-associated cluster in our study.…”

“…As previously described, we detected a high frequency of LOH in the p53 locus, which has been reported as a marker of poor prognosis associated with blastoid variants of MCL [20,21]. Accordingly, Tamaru et al concluded that overexpression of p53 and p27KIP1 may be linked to a cellular mechanism involved in the development of the variant form of MCL [47].…”

“…We could demonstrate a borderline association between genomic alterations of 9q21-q22 and p53 (p=0,052). Such p53 mutations have been described to be associated with variant cytology and predict a poor prognosis [20]. In the present study, alterations of the 9q21 locus were not directly associated to proliferation, but to the proliferationassociated cluster of alterations ( Table 1).…”

“…Blastoid variants of MCL have a high incidence of p53 gene mutations [20,21], p16 INK4a deletions or hypermethylation [14,25,36]. In addition, shorter survival among MCL patients has been correlated with overexpression of c-myc [32] and a high cell proliferation index as measured by immunostaining of other proliferation-associated transcription factors [44].…”

Impact of TP53 mutation and 17p deletion in mantle cell lymphoma

“…1 In one of the larger reports from the Leukemia and Lymphoma Molecular Profiling Project (LLMPP), TP53 mutations were found in 16/82 (20%) of MCL samples and were associated with an unfavorable clinical course. 4 That notwithstanding, the prognostic relevance of 17p deletions (which include the TP53 gene) in MCL is less clear, although several studies have indicated an association with short survival. 5 The aim of this study was to further investigate the mutation profile and prognostic impact of TP53 mutations and 17p deletion in a large cohort of 119 MCL patients collected at university hospitals in Sweden and Finland between 1983 and 2004 (median 1999).…”