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Christian Bastard - One of the best experts on this subject based on the ideXlab platform.
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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
Genes Chromosomes and Cancer, 2012Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian BastardAbstract: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.
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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
Genes Chromosomes and Cancer, 2012Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Sylvain Mareschal, Francoise Parmentier, Jeanmichel Picquenot, Herve Tilly, Christian BastardAbstract: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.
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molecular characterization of 9p21 deletions shows a minimal common deleted region removing cdkn2a exon 1 and CDKN2B exon 2 in diffuse large b cell lymphomas
Genes Chromosomes and Cancer, 2011Co-Authors: Suzan Guney, Fabrice Jardin, Philippe Bertrand, Herve Tilly, Philippe Ruminy, Jean Pierre Kerckaert, Christian BastardAbstract:Diffuse large B cell lymphoma represent the most frequent subtype of non Hodgkin's lymphoma, accounting for 30-40% of cases. Several studies have shown that CDKN2A and CDKN2B deletions are frequent in these lymphomas. These genes encode the P14ARF, CDKN2A, and CDKN2B proteins which play a key role in the control of the G1/S transition of the cell cycle. Using array CGH and a quantitative multiplex PCR method, we have previously identified such deletions in 36% of cases at diagnosis. Using a walking strategy to approach the breakpoints of these deletions we could identify the breakpoints junction of thirteen deletions in 11 patients and of two unbalanced translocation leading to a loss of these genes. A minimal common deleted region of 22.4 kb containing exon 1β of CDKN2A encoding P14ARF and exon 2 of CDKN2B encoding CDKN2B was present in all cases but one. Analysis by quantitative RT PCR showed that the expression level of these genes was decreased in these patients as compared with non deleted cases and that this level was correlated with the deletion status of P14ARF, CDKN2A, and CDKN2B. Analysis of the breakpoint sequences showed that some of them were clustered within a few hundred base-pairs suggesting, even if we failed to identify any clear recombination prone sequences, that in these deletions the rearrangement results from non-random mechanisms.
Ananth C Viswanathan - One of the best experts on this subject based on the ideXlab platform.
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genome wide association study identifies susceptibility loci for open angle glaucoma at tmco1 and CDKN2B as1
Nature Genetics, 2011Co-Authors: Kathryn P Burdon, Stuart Macgregor, Alex W Hewitt, Shiwani Sharma, Glyn Chidlow, Richard A Mills, Patrick Danoy, Robert J Casson, Ananth C ViswanathanAbstract:We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
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genome wide association study identifies susceptibility loci for open angle glaucoma at tmco1 and CDKN2B as1
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Kathryn P Burdon, Stuart Macgregor, Alex W Hewitt, Shiwani Sharma, Glyn Chidlow, Richard A Mills, Patrick Danoy, Robert J Casson, Ananth C Viswanathan, Jimmy Z LiuAbstract:We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10-10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10-9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10-14, OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10-14, OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. © 2011 Nature America, Inc. All rights reserved.
Alex W Hewitt - One of the best experts on this subject based on the ideXlab platform.
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genome wide association study identifies susceptibility loci for open angle glaucoma at tmco1 and CDKN2B as1
Nature Genetics, 2011Co-Authors: Kathryn P Burdon, Stuart Macgregor, Alex W Hewitt, Shiwani Sharma, Glyn Chidlow, Richard A Mills, Patrick Danoy, Robert J Casson, Ananth C ViswanathanAbstract:We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.
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genome wide association study identifies susceptibility loci for open angle glaucoma at tmco1 and CDKN2B as1
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Kathryn P Burdon, Stuart Macgregor, Alex W Hewitt, Shiwani Sharma, Glyn Chidlow, Richard A Mills, Patrick Danoy, Robert J Casson, Ananth C Viswanathan, Jimmy Z LiuAbstract:We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10-10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10-9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10-14, OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10-14, OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. © 2011 Nature America, Inc. All rights reserved.
Philippe Froguel - One of the best experts on this subject based on the ideXlab platform.
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strong association of common variants in the cdkn2a CDKN2B region with type 2 diabetes in french europids
Diabetologia, 2008Co-Authors: Konsta Duesing, Ghazaleh Fatemifar, Guillaume Charpentier, Michel Marre, Jean Tichet, Serge Hercberg, Beverley Balkau, Philippe FroguelAbstract:Aims/hypothesis Genome-wide association studies (GWASs) recently identified common variants in the CDKN2A/CDKN2B region on chromosome 9p as being strongly associated with type 2 diabetes. Since these association signals were not picked up by the French-Canadian GWAS, we sought to replicate these findings in the French Europid population and to further characterise the susceptibility variants at this novel locus.
J Y Delattre - One of the best experts on this subject based on the ideXlab platform.
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genome wide association study identifies five susceptibility loci for glioma
Nature Genetics, 2009Co-Authors: Sanjay Shete, Fay J Hosking, Lindsay B Robertson, Sara E Dobbins, Marc Sanson, Beatrice Malmer, Matthias Simon, Yannick Marie, Blandine Boisselier, J Y DelattreAbstract:To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.