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Several mechanisms lead to the inactivation of the CDKN2A ( P16 ), P14ARF, or CDKN2B ( P15 ) genes in the GCB and ABC molecular DLBCL subtypes
Author(s) -
Guney Suzan,
Jardin Fabrice,
Bertrand Philippe,
Mareschal Sylvain,
Parmentier Françoise,
Picquenot JeanMichel,
Tilly Hervé,
Bastard Christian
Publication year - 2012
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.21970
Subject(s) - p14arf , cdkn2a , methylation , cdkn2b , dna methylation , gene , cancer research , microbiology and biotechnology , locus (genetics) , biology , gene expression , genetics , tumor suppressor gene , carcinogenesis
Diffuse large B‐cell lymphoma (DLBCL) represents the most frequent type of aggressive lymphoma. Deletions of the CDKN2A locus, encoding the proteins CDKN2A (P16), P14ARF, and of the CDKN2B locus, encoding the protein CDKN2B (P15), affect one‐third of DLBCL patients. Although other mechanisms that decrease gene expression have been reported, such as promoter methylation, the prognostic value of these mechanisms is still unclear. We studied the deletion and methylation status of these genes in 171 patients and correlated the genomic results with their mRNA expression level and clinical outcome. CDKN2A , P14ARF , and CDKN2B deletions were significantly correlated with decreased mRNA expression ( P < 0.0001, P < 0.0001, and P = 0.0148, respectively). P14ARF was methylated in only two patients (1.3%), whereas CDKN2A and CDKN2B were methylated in 36.7 and 31.4% of patients, respectively. Methylation levels greater than 25% were associated with decreased expression of CDKN2A ( P = 0.0169). CDKN2A and CDKN2B inactivation by deletion or methylation was observed in 42.7 and 37.4% of cases, respectively. Including P14ARF deletions, we identified an inactivating mechanism for at least one of these genes in 47% of patients. Although gene inactivation was not correlated with the international prognostic index, P14ARF and CDKN2B inactivation was significantly associated with shorter survival ( P = 0.0048 and P = 0.0413, respectively), whereas CDKN2A was not ( P = 0.085). Low mRNA expression levels of these genes were correlated with the ABC phenotype. Furthermore, our results show that an inactivating methylation was more frequent in the GCB phenotype. © 2012 Wiley Periodicals, Inc.