The costimulatory molecule CD70 is regulated by distinct molecular mechanisms and is associated with overall survival in diffuse large B‐cell lymphoma. Issue 8 (28th May 2013)

• Record Type: Journal Article
• Authors: Bertrand, P.; Maingonnat, C.; Penther, D.; Guney, S.; Ruminy, P.; Picquenot, J. M.; Mareschal, S.; Alcantara, M.; Bouzelfen, A.; Dubois, S.; Figeac, M.; Bastard, C.; Tilly, H.; Jardin, F.
• Is Part Of: Genes, chromosomes & cancer. Volume 52:Issue 8(2013:Aug.)
• Page Start: 764
• Page End: 774
• Publication Date: 2013-05-28
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22072
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>In diffuse large B‐cell lymphomas (DLBCL), a recurrent deletion of the 19p13 region has recently been described. <italic>CD70</italic> and <italic>TNFSF9</italic> genes are suspected tumor suppressor genes, but previous studies suggest an oncogenic role for <italic>CD70</italic>. Therefore, we studied the consequences of variation in <italic>CD70</italic> copy number and epigenetic modifications on <italic>CD70</italic> expression. Copy‐number variation was investigated in 144 <italic>de novo</italic> DLBCL tissues by comparative genomic hybridization array and quantitative multiplex PCR. Gene expression was assessed by quantitative RT‐PCR, and <italic>CD70</italic> promoter methylation was determined by pyrosequencing. The 19p13.3.2 region was deleted in 21 (14.6%) cases, which allowed the minimal commonly deleted region of 57 Kb that exclusively includes the <italic>CD70</italic> gene to be defined. Homozygous deletions were observed in four (2.7%) cases, and acquired single‐nucleotide variations of <italic>CD70</italic> were detected in nine (6.3%) cases. <italic>CD70</italic> was highly expressed in both germinal centre B‐cell‐like (GCB) and activated B‐cell‐like (ABC) DLBCL compared to normal tissue, with distinct molecular mechanisms of mRNA expression regulation. A gene dosage effect was observed in the GCB subtype, whereas promoter methylation was the predominant mechanism of down regulation in the ABC subtype. However, high <italic>CD70</italic> expression levels correlated to shorter overall survival in both the GCB (<italic>P</italic> = 0.0021) and the ABC (<italic>P</italic> =0.0158) subtypes. In conclusion, <italic>CD70</italic> is targeted by recurrent deletions, somatic mutations and promoter hypermethylation, but its high level of expression is related to an unfavorable outcome, indicating that this molecule may constitute a potential therapeutic target in selected DLBCL. © 2013 Wiley Periodicals, Inc.</p> </abstract>