23 results on '"Paillerets BB"'
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2. Characteristics, Treatment, and Outcome of Breast Cancers Diagnosed in BRCA1 and BRCA2 Gene Mutation Carriers in Intensive Screening Programs Including Magnetic Resonance Imaging.
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Chéreau E, Uzan C, Balleyguier C, Chevalier J, de Paillerets BB, Caron O, Rimareix F, Mathieu MC, Koskas M, Bourgier C, André F, Dromain C, and Delaloge S
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- 2010
- Full Text
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3. Relationship between genome and epigenome - challenges and requirements for future research
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Almouzni, G., Altucci, L., Amati, B., Ashley, N., Baulcombe, D., Beaujean, N., Bock, C., Bongcam-Rudloff, E., Bousquet, J., Braun, S., Bressac-de Paillerets, B., Bussemakers, M., Clarke, L., Conesa, A., Estivill, X., Fazeli, A., Grgurevic, N., Gut, I., Heijmans, B.T., Hermouet, S., Houwing-Duistermaat, J., Iacobucci, I., Ilas, J., Kandimalla, R., Krauss-Etschmann, S., Lasko, P., Lehmann, S., Lindroth, A., Majdic, G., Marcotte, E., Martinelli, G., Martinet, N., Meyer, E., Miceli, C., Mills, K., Moreno-Villanueva, M., Morvan, G., Nickel, D., Niesler, B., Nowacki, M., Nowak, J., Ossowski, S., Pelizzola, M., Pochet, R., Potocnik, U., Radwanska, M., Raes, J., Rattray, M., Robinson, M.D., Roelen, B., Sauer, S., Schinzer, D., Slagboom, E., Spector, T., Stunnenberg, H.G., Tiligada, E., Torres-Padilla, M.E., Tsonaka, R., Soom, A. van, Vidakovic, M., Widschwendter, M., Dynamique du noyau, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Dip. Patologia generale, Seconda Università di Napoli, Università degli studi di Napoli Federico II, University of Cambridge [UK] (CAM), Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria, Swedish University of Agricultural Sciences (SLU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centro de Genomica, Instituto Valenciano de Investigaciones Agrarias, Universitat Pompeu Fabra [Barcelona], Institute of Biomedicine and Translational Medicine, Department of Pathophysiology, University of Tartu, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Molecular Mechanisms of Chronic Inflammation in Hematological Diseases ( CRCINA - Département INCIT - Equipe 16), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Comprehensive Pneumology Center, Ludwig Maximilians University and Helmholtz Zentrum Muenchen, Member of the German Research Center for Lung Research, Großhadern, Germany, McGill University, GeoBiosphere Science Centre, Lund University [Lund], Biologie Cellulaire et Moleculaire du Transport des Nutriments, Université Henri Poincaré - Nancy 1 (UHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Langues et Civilisations Orientales (Inalco), School of biosciences and biotechnology, Università di Camerino (UNICAM), Haematology Research Group, Queen's University [Belfast] (QUB)-CCRCB, University of Konstanz, Institute of Cell Biology, University of Bern, University of Bern, Laboratoire de Parasitologie, Université Libre de Bruxelles [Bruxelles] (ULB), Vrije Universiteit [Brussels] (VUB), Faculty of Life Sciences [Manchester], University of Manchester [Manchester], Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Centre for Molecular Life Sciences (NCMLS), Department of Molecular Biology, Radboud university [Nijmegen], Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique (CNRS), Department of Gynaecological Oncology, Institute for Women's Health, University College of London [London] (UCL), Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Centro de Genómica - Centre de Genòmica [IVIA], Instituto Valenciano de Investigaciones Agrarias - Institut Valencià d'Investigacions Agraries - Valencian Institute for agricultural Research (IVIA), Universitat Pompeu Fabra [Barcelona] (UPF), Molecular Mechanisms of Chronic Inflammation in Hematological Diseases (CRCINA-ÉQUIPE 16), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), McGill University = Université McGill [Montréal, Canada], Università degli Studi di Camerino (UNICAM), Université libre de Bruxelles (ULB), Vrije Universiteit Brussel (VUB), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), LS Voortplanting Inwendige Ziekten, Sub Celbiologisch lab., Biology of Reproductive Cells, ES/FAH BRC, Almouzni, G, Altucci, Lucia, Amati, B, Ashley, N, Baulcombe, D, Beaujean, N, Bock, C, Bongcam Rudloff, E, Bousquet, J, Braun, S, Paillerets, Bb, Bussemakers, M, Clarke, L, Conesa, A, Estivill, X, Fazeli, A, Grgurević, N, Gut, I, Heijmans, Bt, Hermouet, S, Houwing Duistermaat, J, Iacobucci, I, Ilaš, J, Kandimalla, R, Krauss Etschmann, S, Lasko, P, Lehmann, S, Lindroth, A, Majdič, G, Marcotte, E, Martinelli, G, Martinet, N, Meyer, E, Miceli, C, Mills, K, Moreno Villanueva, M, Morvan, G, Nickel, D, Niesler, B, Nowacki, M, Nowak, J, Ossowski, S, Pelizzola, M, Pochet, R, Potočnik, U, Radwanska, M, Raes, J, Rattray, M, Robinson, Md, Roelen, B, Sauer, S, Schinzer, D, Slagboom, E, Spector, T, Stunnenberg, Hg, Tiligada, E, Torres Padilla, Me, Tsonaka, R, Soom, Av, Vidaković, M, Widschwendter, M., University of Naples Federico II = Università degli studi di Napoli Federico II, École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Università degli Studi di Camerino = University of Camerino (UNICAM), Universität Bern [Bern] (UNIBE), Radboud University [Nijmegen], and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Epigenomics ,[SDV]Life Sciences [q-bio] ,MESH: Epigenomics ,programme de recherche scientifique ,Epigenesis, Genetic ,Epigenome ,Biologie de la reproduction ,MESH: Epigenesis, Genetic ,epidrugs ,génération ,DNA METHYLATION ,ComputingMilieux_MISCELLANEOUS ,Reproductive Biology ,évolution de la maladie ,Genome ,MESH: Genomics ,Biologie du développement ,DEATH ,Genomics ,Development Biology ,CANCER ,MESH: Research ,impact environnemental ,Technology Platforms ,genome ,epigenome ,microbiome ,environment ,STEM-CELLS ,epigenetic ,Biotechnology ,durée de vie ,programme européen ,facteur génétique ,INHIBITION ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Environment ,maladie ,ddc:570 ,Correspondence ,Genetics ,Humans ,cancer ,MESH: Genome ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Veterinary Sciences ,Microbiome ,MESH: Humans ,Research ,santé publique ,570 Life sciences ,biology ,sensibilité aux maladies ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level. ispartof: BMC Genomics vol:15 issue:1 pages:487-487 ispartof: location:England status: published
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- 2014
4. Germline mutation in the NBR1 gene involved in autophagy detected in a family with renal tumors.
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Adolphe F, Ferlicot S, Verkarre V, Posseme K, Couvé S, Garnier P, Droin N, Deloger M, Job B, Giraud S, Paillerets BB, Gardie B, Richard S, Renaud F, and Gad S
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- Adult, Aged, Carcinoma, Renal Cell genetics, Female, Follow-Up Studies, Humans, Kidney Neoplasms genetics, Male, Middle Aged, Pedigree, Prognosis, Autophagy, Carcinoma, Renal Cell pathology, Genetic Predisposition to Disease, Germ-Line Mutation, Intracellular Signaling Peptides and Proteins genetics, Kidney Neoplasms pathology
- Abstract
Hereditary Renal Cell Carcinomas (RCC) are caused by mutations in predisposing genes, the major ones including VHL, FLCN, FH and MET. However, many families with inherited RCC have no germline mutation in these genes. Using Whole Exome Sequencing on germline DNA from a family presenting three different histological renal tumors (an angiomyolipoma, a clear-cell RCC and an oncocytic papillary RCC), we identified a frameshift mutation in the Neighbor of BRCA1 gene 1 (NBR1), segregating with the tumors. NBR1 encodes a cargo receptor protein involved in autophagy. Genetic and functional analyses suggested a pathogenic impact of the mutation. Indeed, functional study performed in renal cell lines showed that the mutation alters NBR1 interactions with some of its partners (such as p62/SQSTM1), leading to a dominant negative effect. This results in an altered autophagic process and an increased proliferative capacity in renal cell lines. Our study suggests that NBR1 may be a new predisposing gene for RCC, however its characterization needs to be further investigated in order to confirm its role in renal carcinogenesis., Competing Interests: Declarations of Competing Interest none, (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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5. FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells.
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Habel N, El-Hachem N, Soysouvanh F, Hadhiri-Bzioueche H, Giuliano S, Nguyen S, Horák P, Gay AS, Debayle D, Nottet N, Béranger G, Paillerets BB, Bertolotto C, and Ballotti R
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- Animals, Cell Line, Tumor, Cell Proliferation, Humans, Melanoma pathology, Mice, Mice, Nude, Transfection, Ubiquitination, Xenograft Model Antitumor Assays, Cellular Reprogramming genetics, Epigenesis, Genetic genetics, Melanoma genetics, Muscle Proteins metabolism, Proteomics methods, SKP Cullin F-Box Protein Ligases metabolism
- Abstract
Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.
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- 2021
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6. Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.
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Walpole S, Pritchard AL, Cebulla CM, Pilarski R, Stautberg M, Davidorf FH, de la Fouchardière A, Cabaret O, Golmard L, Stoppa-Lyonnet D, Garfield E, Njauw CN, Cheung M, Turunen JA, Repo P, Järvinen RS, van Doorn R, Jager MJ, Luyten GPM, Marinkovic M, Chau C, Potrony M, Höiom V, Helgadottir H, Pastorino L, Bruno W, Andreotti V, Dalmasso B, Ciccarese G, Queirolo P, Mastracci L, Wadt K, Kiilgaard JF, Speicher MR, van Poppelen N, Kilic E, Al-Jamal RT, Dianzani I, Betti M, Bergmann C, Santagata S, Dahiya S, Taibjee S, Burke J, Poplawski N, O'Shea SJ, Newton-Bishop J, Adlard J, Adams DJ, Lane AM, Kim I, Klebe S, Racher H, Harbour JW, Nickerson ML, Murali R, Palmer JM, Howlie M, Symmons J, Hamilton H, Warrier S, Glasson W, Johansson P, Robles-Espinoza CD, Ossio R, de Klein A, Puig S, Ghiorzo P, Nielsen M, Kivelä TT, Tsao H, Testa JR, Gerami P, Stern MH, Paillerets BB, Abdel-Rahman MH, and Hayward NK
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- Age of Onset, Alleles, Female, Gene Frequency, Genotype, Humans, Male, Neoplastic Syndromes, Hereditary epidemiology, Phenotype, Risk Assessment, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Neoplastic Syndromes, Hereditary diagnosis, Neoplastic Syndromes, Hereditary genetics, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics
- Abstract
Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors., Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided., Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001)., Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.
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- 2018
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7. Corrigendum: Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort.
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Leman R, Gaildrat P, Gac GL, Ka C, Fichou Y, Audrezet MP, Caux-Moncoutier V, Caputo SM, Boutry-Kryza N, Léone M, Mazoyer S, Bonnet-Dorion F, Sevenet N, Guillaud-Bataille M, Rouleau E, Paillerets BB, Wappenschmidt B, Rossing M, Muller D, Bourdon V, Revillon F, Parsons MT, Rousselin A, Davy G, Castelain G, Castéra L, Sokolowska J, Coulet F, Delnatte C, Férec C, Spurdle AB, Martins A, Krieger S, and Houdayer C
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- 2018
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8. Pattern multiplicity and fumarate hydratase (FH)/S-(2-succino)-cysteine (2SC) staining but not eosinophilic nucleoli with perinucleolar halos differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas from kidney tumors without FH gene alteration.
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Muller M, Guillaud-Bataille M, Salleron J, Genestie C, Deveaux S, Slama A, de Paillerets BB, Richard S, Benusiglio PR, and Ferlicot S
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- Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell pathology, Diagnosis, Differential, Fumarate Hydratase genetics, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Kidney Neoplasms genetics, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Leiomyomatosis genetics, Leiomyomatosis metabolism, Leiomyomatosis pathology, Carcinoma, Renal Cell diagnosis, Fumarate Hydratase metabolism, Kidney Neoplasms diagnosis, Leiomyomatosis diagnosis
- Abstract
Hereditary leiomyomatosis and renal cell carcinoma syndrome is characterized by an increased risk of agressive renal cell carcinoma, often of type 2 papillary histology, and is caused by FH germline mutations. A prominent eosinophilic macronucleolus with a perinucleolar clear halo is distinctive of hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma according to the 2012 ISUP and 2016 WHO kidney tumor classification. From an immunohistochemistry perspective, tumors are often FH-negative and S-(2-succino)-cysteine (2SC) positive. We performed a pathology review of 24 renal tumors in 23 FH mutation carriers, and compared them to 12 type 2 papillary renal cell carcinomas from FH wild-type patients. Prominent eosinophilic nucleoli with perinucleolar halos were present in almost all FH-deficient renal cell carcinomas (23/24). Unexpectedly, they were also present in 58% of type 2 papillary renal cell carcinomas from wild-type patients. Renal cell carcinoma in mutation carriers displayed a complex architecture with multiple patterns, typically papillary, tubulopapillary, and tubulocystic, but also sarcomatoid and rhabdoid. Such pattern diversity was not seen in non-carriers. FH/2SC immunohistochemistry was informative as all hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinomas were either FH- or 2SC+. For FH and 2SC immunohistochemistries taken separately, sensitivity of negative anti-FH immunohistochemistry was 87.5% and specificity was 100%. For positive anti-2SC immunohistochemistry, sensitivity, and specificity were 91.7% and 91.7%, respectively. All FH wild-type renal cell carcinoma were FH-positive, and all but one were 2SC-negative. In conclusion, multiplicity of architectural patterns, rhabdoid/sarcomatoid components and combined FH/2SC staining, but not prominent eosinophilic nucleoli with perinucleolar halos, differentiate hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma from type 2 papillary renal cell carcinoma with efficient FH gene. Our findings are crucial in identifying who should be referred to Cancer Genetics clinics for genetic counseling and testing.
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- 2018
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9. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome.
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Renaux-Petel M, Charbonnier F, Théry JC, Fermey P, Lienard G, Bou J, Coutant S, Vezain M, Kasper E, Fourneaux S, Manase S, Blanluet M, Leheup B, Mansuy L, Champigneulle J, Chappé C, Longy M, Sévenet N, Paillerets BB, Guerrini-Rousseau L, Brugières L, Caron O, Sabourin JC, Tournier I, Baert-Desurmont S, Frébourg T, and Bougeard G
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- Adrenocortical Carcinoma blood, Adrenocortical Carcinoma genetics, Adrenocortical Carcinoma pathology, Adult, Breast Neoplasms blood, Breast Neoplasms genetics, Breast Neoplasms pathology, Child, Choroid Plexus Neoplasms blood, Choroid Plexus Neoplasms genetics, Choroid Plexus Neoplasms pathology, Female, Germ-Line Mutation genetics, Humans, Li-Fraumeni Syndrome blood, Li-Fraumeni Syndrome pathology, Male, Middle Aged, Mosaicism, Tumor Suppressor Protein p53 blood, Young Adult, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Li-Fraumeni Syndrome genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Background: Development of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS., Methods and Results: Among 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35., Conclusions: This study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
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- 2018
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10. A germline oncogenic MITF mutation and tumor susceptibility.
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Paillerets BB, Lesueur F, and Bertolotto C
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- Carcinogenesis genetics, Carcinoma, Renal Cell complications, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Genetic Predisposition to Disease, Humans, Kidney Neoplasms complications, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Melanoma complications, Melanoma pathology, Skin Neoplasms complications, Skin Neoplasms pathology, Sumoylation, Melanoma, Cutaneous Malignant, Germ-Line Mutation, Melanoma genetics, Microphthalmia-Associated Transcription Factor genetics, Skin Neoplasms genetics
- Abstract
MITF (Microphthalmia-associated transcription factor) is a lineage specific transcription factor that plays a critical role in melanocyte homeostasis and whose deregulation has been shown to contribute to melanoma disease. A germline mutation in MITF, impairing SUMOylation and predisposing to cutaneous malignant melanoma, was recently identified. Interestingly, an association of the MITF mutation with coexisting melanoma and renal cell carcinoma was also shown. Collectively, these data suggest that MITF has an important oncogenic function in tumorigenesis of multiple tissues/melanocytes and kidney cells., (Copyright © 2013 Elsevier GmbH. All rights reserved.)
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- 2014
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11. Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.
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Pujol P, Lyonnet DS, Frebourg T, Blin J, Picot MC, Lasset C, Dugast C, Berthet P, de Paillerets BB, Sobol H, Grandjouan S, Soubrier F, Buecher B, Guimbaud R, Lidereau R, Jonveaux P, Houdayer C, Giraud S, Olschwang S, Nogue E, Galibert V, Bara C, Nowak F, Khayat D, and Nogues C
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- Breast Neoplasms prevention & control, Cancer Care Facilities statistics & numerical data, Colorectal Neoplasms, Hereditary Nonpolyposis prevention & control, DNA Mismatch Repair genetics, DNA Mutational Analysis statistics & numerical data, Family Health, Female, France, Genetic Carrier Screening, Genetic Counseling trends, Genetic Testing trends, Humans, Laboratories statistics & numerical data, Male, MutL Protein Homolog 1, Mutation, Neoplastic Syndromes, Hereditary prevention & control, Ovarian Neoplasms prevention & control, Referral and Consultation trends, Adaptor Proteins, Signal Transducing genetics, Breast Neoplasms genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins genetics, Genes, BRCA1, Genes, BRCA2, Genetic Counseling statistics & numerical data, Genetic Testing statistics & numerical data, MutS Homolog 2 Protein genetics, Neoplastic Syndromes, Hereditary genetics, Nuclear Proteins genetics, Ovarian Neoplasms genetics, Referral and Consultation statistics & numerical data
- Abstract
Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.
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- 2013
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12. Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history.
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Ghiorzo P, Pastorino L, Queirolo P, Bruno W, Tibiletti MG, Nasti S, Andreotti V, Paillerets BB, and Bianchi Scarrà G
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- Case-Control Studies, Family, Female, Humans, Italy, Male, Pedigree, Prevalence, Skin Neoplasms pathology, Amino Acid Substitution genetics, Genetic Predisposition to Disease, Germ-Line Mutation genetics, Melanoma genetics, Melanoma pathology, Microphthalmia-Associated Transcription Factor genetics, Skin Neoplasms genetics
- Abstract
A French and an Australian study have recently identified a rare germline functional variant in the microphthalmia-associated transcription factor (MITF) (E318K) that predisposes to familial and sporadic melanoma and to renal cell carcinoma (RCC), showing a new link between two tumour types with different risk factors and between deregulated sumoylation and cancer. The aim of this study was to test the prevalence of the MITF E318K mutation in 667 Italian melanoma patients. We observed significant associations between histological subtypes and family cancer history. Carriers exhibited a nearly threefold higher risk of developing melanoma compared with controls. Carriers were also more likely to have developed multiple primary melanomas (6.40-fold), compared with wt patients. Carriers with a personal and/or family history of pancreatic cancer and kidney cancer had a nearly 31- and eightfold higher risk of developing melanoma compared with wt patients. Our findings further support MITF as a medium-penetrance melanoma susceptibility gene, highlight a potential association with histological subtypes and suggest that MITF may predispose to pancreatic cancer., (© 2012 John Wiley & Sons A/S.)
- Published
- 2013
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13. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma.
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Postel-Vinay S, Véron AS, Tirode F, Pierron G, Reynaud S, Kovar H, Oberlin O, Lapouble E, Ballet S, Lucchesi C, Kontny U, González-Neira A, Picci P, Alonso J, Patino-Garcia A, de Paillerets BB, Laud K, Dina C, Froguel P, Clavel-Chapelon F, Doz F, Michon J, Chanock SJ, Thomas G, Cox DG, and Delattre O
- Subjects
- France, Genome-Wide Association Study, Genotype, Haplotypes genetics, Humans, Logistic Models, Odds Ratio, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide genetics, Sarcoma, Ewing ethnology, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 10 genetics, Chromosomes, Human, Pair 15 genetics, DNA-Binding Proteins genetics, Early Growth Response Protein 2 genetics, Genetic Predisposition to Disease genetics, Sarcoma, Ewing genetics
- Abstract
Ewing sarcoma, a pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. We performed a genome-wide association study (GWAS) of 401 French individuals with Ewing sarcoma, 684 unaffected French individuals and 3,668 unaffected individuals of European descent and living in the United States. We identified candidate risk loci at 1p36.22, 10q21 and 15q15. We replicated these loci in two independent sets of cases and controls. Joint analysis identified associations with rs9430161 (P = 1.4 × 10(-20); odds ratio (OR) = 2.2) located 25 kb upstream of TARDBP, rs224278 (P = 4.0 × 10(-17); OR = 1.7) located 5 kb upstream of EGR2 and, to a lesser extent, rs4924410 at 15q15 (P = 6.6 × 10(-9); OR = 1.5). The major risk haplotypes were less prevalent in Africans, suggesting that these loci could contribute to geographical differences in Ewing sarcoma incidence. TARDBP shares structural similarities with EWSR1 and FUS, which encode RNA binding proteins, and EGR2 is a target gene of EWSR1-ETS. Variants at these loci were associated with expression levels of TARDBP, ADO (encoding cysteamine dioxygenase) and EGR2.
- Published
- 2012
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14. International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation.
- Author
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Peixoto A, Santos C, Pinheiro M, Pinto P, Soares MJ, Rocha P, Gusmão L, Amorim A, van der Hout A, Gerdes AM, Thomassen M, Kruse TA, Cruger D, Sunde L, Bignon YJ, Uhrhammer N, Cornil L, Rouleau E, Lidereau R, Yannoukakos D, Pertesi M, Narod S, Royer R, Costa MM, Lazaro C, Feliubadaló L, Graña B, Blanco I, de la Hoya M, Caldés T, Maillet P, Benais-Pont G, Pardo B, Laitman Y, Friedman E, Velasco EA, Durán M, Miramar MD, Valle AR, Calvo MT, Vega A, Blanco A, Diez O, Gutiérrez-Enríquez S, Balmaña J, Ramon y Cajal T, Alonso C, Baiget M, Foulkes W, Tischkowitz M, Kyle R, Sabbaghian N, Ashton-Prolla P, Ewald IP, Rajkumar T, Mota-Vieira L, Giannini G, Gulino A, Achatz MI, Carraro DM, de Paillerets BB, Remenieras A, Benson C, Casadei S, King MC, Teugels E, and Teixeira MR
- Subjects
- Amino Acid Sequence, Female, Founder Effect, Genetic Predisposition to Disease, Genetic Testing, Genetics, Population, Humans, Microsatellite Repeats, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Portugal epidemiology, RNA, Messenger analysis, Reading Frames genetics, Sequence Deletion, Breast Neoplasms epidemiology, Breast Neoplasms genetics, Genes, BRCA2, Mutation, Ovarian Neoplasms epidemiology, Ovarian Neoplasms genetics
- Abstract
The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer (HBOC) families of Portuguese origin. Since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought, we screened for this rearrangement in a total of 5,443 suspected HBOC families from several countries. Whereas the c.156_157insAlu BRCA2 mutation was detected in 11 of 149 suspected HBOC families from Portugal, representing 37.9% of all deleterious mutations, in other countries it was detected only in one proband living in France and in four individuals requesting predictive testing living in France and in the USA, all being Portuguese immigrants. After performing an extensive haplotype study in carrier families, we estimate that this founder mutation occurred 558 ± 215 years ago. We further demonstrate significant quantitative differences regarding the production of the BRCA2 full length RNA and the transcript lacking exon 3 in c.156_157insAlu BRCA2 mutation carriers and in controls. The cumulative incidence of breast cancer in carriers did not differ from that of other BRCA2 and BRCA1 pathogenic mutations. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement.
- Published
- 2011
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15. Factors associated with altered long-term well-being after prophylactic salpingo-oophorectomy among women at increased hereditary risk for breast and ovarian cancer.
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Touboul C, Uzan C, Ichanté JL, Caron O, Dunant A, Dauchy S, Gouy S, de Paillerets BB, Morice P, and Delaloge S
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- Adult, Aged, Breast Neoplasms genetics, Female, Genetic Predisposition to Disease, Humans, Middle Aged, Multivariate Analysis, Ovarian Neoplasms genetics, Quality of Life, Risk Assessment, Risk Factors, Breast Neoplasms prevention & control, Fallopian Tubes surgery, Ovarian Neoplasms prevention & control, Ovariectomy methods
- Abstract
Background: Prophylactic bilateral salpingo-oophorectomy (PBSO) might alter several components of well-being, such as sexual functioning and endocrine symptoms, in women at high risk for hereditary breast and/or ovarian cancer, compared with the general population. We searched for factors associated with altered long-term well-being in this population (lower quality of life [QOL], altered sexual functioning, greater anxiety, more endocrine symptoms)., Methods: All high-risk women who had undergone PBSO during the past 15 years in a single cancer center were contacted by mail. Upon acceptance, they were sent five questionnaires: (a) general social questions, (b) the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, (c) Sexual Activity Questionnaire, (d) Functional Assessment of Cancer Therapy - Endocrine Symptom, and (5) State-Trait Anxiety Inventory. Logistic analyses were used to identify factors associated with altered results. Because of multiple testing, only p-values ≤ .01 were considered significant., Results: One hundred twelve of 175 women (64%) returned the completed questionnaires at a mean duration (standard deviation) of 6.0 (5.1) years after PBSO. QOL was positively influenced by two baseline factors: a high educational level and occupying an executive position. However, younger age at PBSO was associated with lower social functioning and greater anxiety. At the time of the study, practicing a sport and the avoidance of weight gain (≥10%) were highly related to QOL, sexual pleasure, endocrine symptoms, and anxiety in the univariate analysis and predictive of better QOL and lower anxiety in the multivariate analysis., Conclusions: Younger women and women with a low educational level and no occupation appear to be at higher risk for altered long-term well-being. After surgery, practicing a sport and stable weight may help maintain overall well-being.
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- 2011
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16. Characteristics of the coexistence of melanoma and renal cell carcinoma.
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Maubec E, Chaudru V, Mohamdi H, Grange F, Patard JJ, Dalle S, Crickx B, Paillerets BB, Demenais F, and Avril MF
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- Adult, Aged, Carcinoma, Renal Cell genetics, Cyclin-Dependent Kinase 4, Family Health, Female, Genes, p16, Genetic Predisposition to Disease, Humans, Kidney Neoplasms genetics, Male, Melanoma genetics, Middle Aged, Neoplasms, Multiple Primary genetics, Risk Factors, Skin Neoplasms diagnosis, Skin Neoplasms genetics, Carcinoma, Renal Cell diagnosis, Kidney Neoplasms diagnosis, Melanoma diagnosis, Neoplasms, Multiple Primary diagnosis
- Abstract
Background: Patients with melanoma (MM) have an increased risk of kidney cancer, and there is an excess risk of MM among patients with renal cell carcinoma (RCC). The objective of the current study was to analyze a series of 42 patients with both MM and RCC to identify clinical and pathologic features as well as risk factors of this association., Methods: Clinical and pathologic characteristics of 42 patients who developed both MM and RCC (the MM + RCC series) were compared with 2 published series in each cancer alone: a series of 293 patients with MM (MM series) and a series of 1527 patients with RCC (RCC series)., Results: RCC was diagnosed concomitantly or after MM in 83% of patients in the MM + RCC series. Those patients displayed a high proportion of asymptomatic RCC at diagnosis (70%) and a higher frequency of stage I tumors (61%) than patients in the RCC series. Compared with the MM series, patients in the MM + RCC series more often were men, had a higher frequency of blond/red hair, had poor tanning ability, and had a higher number of nevi. In addition, patients in the MM + RCC series had a high aggregation of other malignancies (mainly skin cancers) and a significantly higher frequency of family history of MM (P = .005). Only 2 cyclin-dependent kinase 2A gene (CDKN2A) germline mutations were identified among patients in the MM + RCC series who also were members of MM-prone families., Conclusions: The high aggregation of cancers among patients in the MM + RCC series and the familial clustering of MM argued for a genetic predisposition that may be partly independent of CDKN2A., (Cancer 2010. © 2010 American Cancer Society.)
- Published
- 2010
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17. Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations.
- Author
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Brugières L, Pierron G, Chompret A, Paillerets BB, Di Rocco F, Varlet P, Pierre-Kahn A, Caron O, Grill J, and Delattre O
- Subjects
- Adult, Child, Preschool, DNA Mutational Analysis, Family, Female, Genetic Predisposition to Disease, Humans, Infant, Male, Pedigree, Cerebellar Neoplasms genetics, Germ-Line Mutation, Medulloblastoma genetics, Penetrance, Repressor Proteins genetics
- Abstract
Methods and Results: Germline SUFU mutations were identified in two families with several children under 3 years of age diagnosed with medulloblastoma. All medulloblastomas in which the histology was reviewed were of the desmoplastic subtype, including three with the rare extensive nodularity subtype. In both families, the mutation detected in the SUFU gene was a frameshift mutation. Among the 25 mutation carriers identified in the two families, seven developed medulloblastomas., Conclusions: This report highlights three features of SUFU related tumours. These are mainly medulloblastomas with extensive nodularity or typical desmoplastic/nodular medulloblastomas. These tumours mostly, if not exclusively, appear during the first 3 years of life. The penetrance of the mutation is incomplete.
- Published
- 2010
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18. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families.
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Bougeard G, Sesboüé R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugières L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D, Bonaïti-Pellié C, and Frébourg T
- Subjects
- Female, France, Gene Deletion, Humans, Male, Mutation, Missense, Neoplasms genetics, Pedigree, Genes, p53, Genetic Predisposition to Disease, Li-Fraumeni Syndrome genetics
- Abstract
We have performed an extensive analysis of TP53 in 474 French families suggestive of Li-Fraumeni syndrome (LFS), including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%), and we identified in four families genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplodeficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9 year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.
- Published
- 2008
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19. Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries.
- Author
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Goldstein AM, Chaudru V, Ghiorzo P, Badenas C, Malvehy J, Pastorino L, Laud K, Hulley B, Avril MF, Puig-Butille JA, Miniere A, Marti R, Chompret A, Cuellar F, Kolm I, Mila M, Tucker MA, Demenais F, Bianchi-Scarra G, Puig S, and de-Paillerets BB
- Subjects
- Adult, Case-Control Studies, Dysplastic Nevus Syndrome epidemiology, Eye Color, Female, France, Gene Frequency, Genotype, Hair Color, Heterozygote, Humans, Italy, Male, Mutation, Phenotype, Polymorphism, Genetic, Spain, United States, Genes, p16, Melanoma genetics, Receptor, Melanocortin, Type 1 genetics, Skin Neoplasms genetics, Skin Pigmentation
- Abstract
The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had > or =2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered.
- Published
- 2007
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20. Significant contribution of germline BRCA2 rearrangements in male breast cancer families.
- Author
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Tournier I, Paillerets BB, Sobol H, Stoppa-Lyonnet D, Lidereau R, Barrois M, Mazoyer S, Coulet F, Hardouin A, Chompret A, Lortholary A, Chappuis P, Bourdon V, Bonadona V, Maugard C, Gilbert B, Nogues C, Frébourg T, and Tosi M
- Subjects
- Humans, Male, Mutation, Breast Neoplasms, Male genetics, Gene Rearrangement, Genes, BRCA2
- Abstract
Although screening for large deletions or duplications of the BRCA1 gene is becoming a routine component of the molecular diagnosis of familial breast cancer, little is known about the occurrence of such rearrangements in the BRCA2 gene. Because of the high frequency of BRCA2 mutations in breast cancer families with at least one case of male breast cancer, we selected a cohort of 39 such families, tested negative for mutations in the coding regions of BRCA1 and BRCA2, and developed an assay for BRCA2 rearrangements, based on quantitative multiplex PCR of short fluorescent fragments (QMPSF). We found three rearrangements: (1) a deletion of exons 12 and 13; (2) a duplication of exons 1 and 2; and (3) a complete deletion of BRCA2. We determined the boundaries of the deletion of exons 12 and 13, showing that it resulted from an unequal recombination between Alu sequences. We mapped the complete BRCA2 deletion, which extends over at least 298 kb and showed that it does not affect APRIN/AS3, previously characterized as a tumor suppressor gene, but it comprises several loci corresponding to proven or putative transcripts of unknown functional significance. These data suggest that screening for BRCA2 rearrangements should be done, especially in male breast cancer families tested negative for BRCA1 and BRCA2 mutations.
- Published
- 2004
- Full Text
- View/download PDF
21. The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.
- Author
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Foulkes WD, Thiffault I, Gruber SB, Horwitz M, Hamel N, Lee C, Shia J, Markowitz A, Figer A, Friedman E, Farber D, Greenwood CM, Bonner JD, Nafa K, Walsh T, Marcus V, Tomsho L, Gebert J, Macrae FA, Gaff CL, Paillerets BB, Gregersen PK, Weitzel JN, Gordon PH, MacNamara E, King MC, Hampel H, De La Chapelle A, Boyd J, Offit K, Rennert G, Chong G, and Ellis NA
- Subjects
- Alanine genetics, Case-Control Studies, Chromosomes, Human, Pair 2 genetics, Crystallography, X-Ray, Female, Gene Frequency genetics, Haplotypes genetics, Heterozygote, Humans, Israel, Male, Microsatellite Repeats genetics, MutS Homolog 2 Protein, Mutation, Missense genetics, Neoplasms genetics, Pedigree, Polymorphism, Genetic genetics, Proline genetics, Protein Conformation, Proto-Oncogene Proteins analysis, Proto-Oncogene Proteins chemistry, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins, Founder Effect, Genetic Predisposition to Disease, Jews genetics, Point Mutation genetics, Proto-Oncogene Proteins genetics
- Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.
- Published
- 2002
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22. [Evolution of cancer markers: from radio-immunology to DNA chips and from surveillance to forecasting].
- Author
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Bellet D, Lazar V, de Paillerets BB, Bennaceur-Griscelli A, Bénard J, and Bidart JM
- Subjects
- Forecasting, Genetic Markers genetics, Genetic Predisposition to Disease genetics, Humans, Neoplasm Proteins analysis, Neoplasms genetics, Oligonucleotide Array Sequence Analysis trends, Prostate-Specific Antigen analysis, Biomarkers, Tumor analysis, Neoplasms chemistry
- Published
- 2000
23. Resistance of MCF7 human breast carcinoma cells to TNF-induced cell death is associated with loss of p53 function.
- Author
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Cai Z, Capoulade C, Moyret-Lalle C, Amor-Gueret M, Feunteun J, Larsen AK, Paillerets BB, and Chouaib S
- Subjects
- Cyclin-Dependent Kinase Inhibitor p21, Cyclins genetics, Drug Resistance, Neoplasm, G1 Phase drug effects, G1 Phase radiation effects, Genes, Viral, Humans, Mutation, Papillomaviridae genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins c-mdm2, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53 biosynthesis, Viral Structural Proteins genetics, Apoptosis drug effects, Breast Neoplasms genetics, Breast Neoplasms pathology, Genes, p53, Nuclear Proteins, Tumor Necrosis Factor-alpha pharmacology
- Abstract
We have investigated the relationship between the development of tumor resistance towards the cytotoxic action of tumor necrosis factor-alpha (TNF) and p53 function, using the TNF-sensitive MCF7 human breast adenocarcinoma cell line and two TNF-resistant sublines, MCF7/R-A1 and MCF7/Adr. Use of single-strand conformation polymorphism (SSCP) analysis and DNA sequencing shows that MCF7 has a wild-type p53 gene, whereas both TNF-resistant sublines exhibit mutant p53. This includes a point mutation R280K in MCF7/R-A1 cells, and a point mutation at the splicing acceptor site on the upstream border of exon 5 resulting in a 21 pb deletion in MCF7/Adr cells. These mutations result in loss of p53 capacity to transactivate FASAY (functional assay in yeast). In contrast to what is observed for parental MCF7 cells, treatment of resistant sublines with TNF or gamma-irradiation fails neither to induce the expression of the p53-regulated gene products p21waf1/CIP1 and MDM2, nor to arrest the cells in the G1 phase of the cell cycle. Disruption of p53 wild-type function in MCF7 cells by transfection with human papillomavirus type-16 E6 gene, leads to abrogation of the cytotoxic, but not the cytostatic activity of TNF. Altogether, our results strongly suggest that wild-type p53 is involved in cytotoxic action of TNF, and point out that loss of p53 function contributes to resistance of tumor cell to TNF-induced killing.
- Published
- 1997
- Full Text
- View/download PDF
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