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Christian Bastard - One of the best experts on this subject based on the ideXlab platform.

  • several mechanisms lead to the inactivation of the cdkn2a p16 P14arf or cdkn2b p15 genes in the gcb and abc molecular dlbcl subtypes
    Genes Chromosomes and Cancer, 2012
    Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian Bastard
    Abstract:

    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.

  • several mechanisms lead to the inactivation of the cdkn2a p16 P14arf or cdkn2b p15 genes in the gcb and abc molecular dlbcl subtypes
    Genes Chromosomes and Cancer, 2012
    Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian Bastard
    Abstract:

    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.

Sylvain Mareschal - One of the best experts on this subject based on the ideXlab platform.

  • several mechanisms lead to the inactivation of the cdkn2a p16 P14arf or cdkn2b p15 genes in the gcb and abc molecular dlbcl subtypes
    Genes Chromosomes and Cancer, 2012
    Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian Bastard
    Abstract:

    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.

  • several mechanisms lead to the inactivation of the cdkn2a p16 P14arf or cdkn2b p15 genes in the gcb and abc molecular dlbcl subtypes
    Genes Chromosomes and Cancer, 2012
    Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian Bastard
    Abstract:

    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.

Marc Ladanyi - One of the best experts on this subject based on the ideXlab platform.

  • ewing sarcomas with p53 mutation or p16 P14arf homozygous deletion a highly lethal subset associated with poor chemoresponse
    Journal of Clinical Oncology, 2005
    Co-Authors: Hsuanying Huang, Peter B Illei, Zhiquan Zhao, Madhu Mazumdar, Andrew G Huvos, John H Healey, Leonard H Wexler, Richard Gorlick, Paul A Meyers, Marc Ladanyi
    Abstract:

    PURPOSE: EWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/P14arf have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic analysis of these three molecular parameters in ES. PATIENTS AND METHODS: We studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/P14arf, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively. RESULTS: Eight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/P14arf deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/P14arf showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutation alone (P < .001), either p53 or p16/P14arf alteration (P < .001), and stage (P < .01). In multivariate analysis, alterations of p53 and/or p16/P14arf as a single variable, was the most adverse prognostic factor (P < .001), followed by stage (P = .04). In a multivariate analysis with alterations of p53 and p16/P14arf as separate variables, both were significant (P < .001 and P = .03, respectively). Six cases with p16/P14arf deletion were also studied for co-deletion of the contiguous methylthioadenosine phosphorylase gene, and this was detected in four cases. CONCLUSION: Alterations in p53 or p16/P14arf are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse.

  • ewing sarcomas with p53 mutation or p16 P14arf homozygous deletion a highly lethal subset associated with poor chemoresponse
    Journal of Clinical Oncology, 2005
    Co-Authors: Hsuanying Huang, Peter B Illei, Zhiquan Zhao, Madhu Mazumdar, Andrew G Huvos, John H Healey, Leonard H Wexler, Richard Gorlick, Paul A Meyers, Marc Ladanyi
    Abstract:

    Purpose EWS-FLI1 fusion type, p53 mutation, and homozygous deletion of p16/P14arf have each been shown to be prognostically significant in Ewing sarcoma (ES). We provide the first combined prognostic analysis of these three molecular parameters in ES. Patients and Methods We studied 60 patients with ES (stage: localized in 54, metastatic in six). All cases were confirmed to contain the EWS-FLI1 (29 type 1, 12 type 2, 14 other types) or EWS-ERG fusions (five cases). Homozygous deletion of p16/P14arf, and p53 mutations were determined by fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) p53 GeneChip microarray hybridization, respectively. Results Eight cases (13.3%) contained point mutations of p53, and eight cases (13.3%) showed p16/P14arf deletion, including one case with both alterations. Among 32 cases with data on histologic chemoresponse, all 10 with alterations in p53 or p16/P14arf showed a poor chemoresponse (P = .03). Variables predicting poorer overall survival included p53 mutati...

Thomas J Knobloch - One of the best experts on this subject based on the ideXlab platform.

  • deletion of rdink4 arf enhancer a novel mutation to inactivate the ink4 arf locus
    DNA Repair, 2017
    Co-Authors: Ming Poi, Thomas J Knobloch
    Abstract:

    The presence of an enhancer element, RDINK4/ARF (RD), in the prominent INK4-ARF locus provides a novel en bloc mechanism to simultaneously regulate the transcription of the p15INK4B (p15), p16INK4A (p16), and P14arf tumor suppressor genes. While genetic inactivation of p15, p16, and P14arf in human cancers has been extensively studied, little is known about RD alteration and its potential contributions to cancer progression. In this review, we discuss recent developments in RD alteration and its association with p15, p16, and P14arf alterations in human cancers, and demonstrate that RD deletion may represent a novel mechanism to simultaneously down-regulate p15, p16, and P14arf, thus promoting carcinogenesis.

  • alterations of p16ink4a and P14arf in patients with severe oral epithelial dysplasia
    Cancer Research, 2002
    Co-Authors: Laura A Kresty, Thomas J Knobloch, Susan R Mallery, Huijuan Song, Mary Lloyd, Bruce C Casto, Christopher M Weghorst
    Abstract:

    A number of genetic aberrations have been reported in end-stage squamous cell carcinoma of the head and neck, including p16INK4a and P14arf (INK4a/ARF) inactivation rates of 70–85%. Still, the cell cycle-regulatory genes p16INK4a and P14arf remain poorly understood in oral cavity premalignant lesions. This study evaluated INK4a/ARF locus alterations in 26 patients (28 samples) deemed to be at increased risk for malignant transformation to squamous cell carcinoma due to the diagnosis of severe oral epithelial dysplasia. Microscopically confirmed dysplastic oral epithelium and matching normal tissue were laser capture-microdissected from paraffin sections, DNA was isolated, and molecular techniques were used to evaluate p16INK4a and P14arf gene deletion, mutation, loss of heterozygosity (LOH), and hypermethylation events. Deletion of exon 1β, 1α, or 2 was detected in 3.8%, 11.5%, and 7.7% of patients, respectively. INK4a and ARF mutations were detected in 15.4% and 11.5% of patients with severe dysplasia of the oral epithelium. All identified mutations occurred in the INK4a/ARF conserved exon 2. Allelic imbalance was assessed using three markers previously reported to show high LOH rates in head and neck tumors. LOH was found in 42.1%, 35.0%, and 82.4% of patients for the markers IFNα, D9S1748, and D9S171, respectively. Hypermethylation of p16INK4a and P14arf was detected in 57.7% and 3.8% of patients, respectively, using nested, two-stage methylation-specific PCR. The highest rates of p16INK4a hypermethylation occurred in lesions of the tongue and floor of the mouth. In addition, p16INK4a hypermethylation was significantly linked to LOH in two or more markers. These data support that INK4a/ARF locus alterations are frequent events preceding the development of oral cancer and that p16INK4a inactivation occurs to a greater extent in oral dysplasia than does P14arf inactivation.

Suzan Guney - One of the best experts on this subject based on the ideXlab platform.

  • several mechanisms lead to the inactivation of the cdkn2a p16 P14arf or cdkn2b p15 genes in the gcb and abc molecular dlbcl subtypes
    Genes Chromosomes and Cancer, 2012
    Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian Bastard
    Abstract:

    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.

  • several mechanisms lead to the inactivation of the cdkn2a p16 P14arf or cdkn2b p15 genes in the gcb and abc molecular dlbcl subtypes
    Genes Chromosomes and Cancer, 2012
    Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian Bastard
    Abstract:

    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.