Author: "Marinus J. Blok" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Marinus J. Blok"' showing total 71 results

Start Over Author "Marinus J. Blok"

71 results on '"Marinus J. Blok"'

1. Genome sequencing as a generic diagnostic strategy for rare disease

Author: Gaby Schobers, Ronny Derks, Amber den Ouden, Hilde Swinkels, Jeroen van Reeuwijk, Ermanno Bosgoed, Dorien Lugtenberg, Su Ming Sun, Jordi Corominas Galbany, Marjan Weiss, Marinus J. Blok, Richelle A. C. M. Olde Keizer, Tom Hofste, Debby Hellebrekers, Nicole de Leeuw, Alexander Stegmann, Erik-Jan Kamsteeg, Aimee D. C. Paulussen, Marjolijn J. L. Ligtenberg, Xiangqun Zheng Bradley, John Peden, Alejandra Gutierrez, Adam Pullen, Tom Payne, Christian Gilissen, Arthur van den Wijngaard, Han G. Brunner, Marcel Nelen, Helger G. Yntema, and Lisenka E. L. M. Vissers
Subjects: Rare disease, Genome sequencing, Impact modeling, Reducing workflow complexity, Genetic diagnostic laboratories, Germline variant detection, Medicine, Genetics, QH426-470
Abstract: Abstract Background To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease. Methods We performed short-read GS (NovaSeq™6000; 150 bp paired-end reads, 37 × mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels
Published: 2024
Full Text: View/download PDF

2. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Author: Christopher Hakkaart, John F. Pearson, Louise Marquart, Joe Dennis, George A. R. Wiggins, Daniel R. Barnes, Bridget A. Robinson, Peter D. Mace, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Sami Belhadj, Lieke Berger, Marinus J. Blok, Susanne E. Boonen, Julika Borde, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Wendy K. Chung, Kathleen B. M. Claes, GEMO Study Collaborators, EMBRACE Collaborators, Marie-Agnès Collonge-Rame, Jackie Cook, Casey Cosgrove, Fergus J. Couch, Mary B. Daly, Sita Dandiker, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Mallika Dhawan, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Douglas F. Easton, Hans Ehrencrona, Christoph Engel, D. Gareth Evans, Ulrike Faust, Lidia Feliubadaló, Florentia Fostira, Eitan Friedman, Megan Frone, Debra Frost, Judy Garber, Simon A. Gayther, Andrea Gehrig, Paul Gesta, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Eric Hahnen, Christopher R. Hake, Ute Hamann, Thomas V. O. Hansen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Peter J. Hulick, Evgeny N. Imyanitov, SWE-BRCA Investigators, kConFab Investigators, HEBON Investigators, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Zoe Kemp, Judy Kirk, Irene Konstantopoulou, Marco Koudijs, Ava Kwong, Yael Laitman, Fiona Lalloo, Christine Lasset, Charlotte Lautrup, Conxi Lazaro, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Phuong L. Mai, Siranoush Manoukian, Véronique Mari, John W. M. Martens, Lesley McGuffog, Noura Mebirouk, Alfons Meindl, Austin Miller, Marco Montagna, Lidia Moserle, Emmanuelle Mouret-Fourme, Hannah Musgrave, Sophie Nambot, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Tu Nguyen-Dumont, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Pedro Perez-Segura, Paolo Peterlongo, Timea Pocza, Paolo Radice, Juliane Ramser, Johanna Rantala, Gustavo C. Rodriguez, Karina Rønlund, Efraim H. Rosenberg, Maria Rossing, Rita K. Schmutzler, Payal D. Shah, Saba Sharif, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Katie Snape, Doris Steinemann, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Alison H. Trainer, Vishakha Tripathi, Nadine Tung, Klaartje van Engelen, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Lisa Walker, Jeffrey N. Weitzel, Marike R. Wevers, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, and Logan C. Walker
Subjects: Biology (General), QH301-705.5
Abstract: The risk of germline copy number variants (CNVs) in BRCA1 and BRCA2 pathogenic variant carriers in breast cancer is assessed, with CNVs overlapping SULT1A1 decreasing breast cancer risk in BRCA1 carriers.
Published: 2022
Full Text: View/download PDF

3. Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes

Author: Sietse M. Aukema, Selina Glaser, Mari F. C. M. van den Hout, Sonja Dahlum, Marinus J. Blok, Morten Hillmer, Julia Kolarova, Raf Sciot, Dina A. Schott, Reiner Siebert, and Constance T. R. M. Stumpel
Subjects: GENETIC LANDSCAPE, Cancer Research, Kabuki syndrome, CHILDHOOD-CANCER, KMT2D, DNA, UNIPARENTAL DISOMY, Methylation, CLONAL EVOLUTION, GENOMIC ANALYSIS, PEDIATRIC CANCER PREDISPOSITION, Oncology, KDM6A MUTATIONS, Tumor predisposition, Rhabdomyosarcoma, METHYLTRANSFERASE KMT2D SUSTAINS, Genetics, NON-HODGKIN-LYMPHOMA, Genetics (clinical)
Abstract: Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5–10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.
Published: 2022
Full Text: View/download PDF

4. Supplementary Tables 1-4 from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: PDF file - 90K
Published: 2023
Full Text: View/download PDF

5. Data from Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Jacques Simard, Kenneth Offit, Georgia Chenevix-Trench, Douglas F. Easton, Phuong L. Mai, Mark H. Greene, Paolo Radice, Liliana Varesco, Giuseppe Giannini, Alessandra Viel, Loris Bernard, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Peterlongo, V. Shane Pankratz, Zachary Fredericksen, Noralane M. Lindor, Yuan Chun Ding, Susan L. Neuhausen, Amanda B. Spurdle, Marc D. Tischkowitz, Heli Nevanlinna, Taru A. Muranen, Miguel de la Hoya, Trinidad Caldes, Wolfram Heinritz, Britta Fiebig, Karin Kast, Christian Sutter, Andrea Gehrig, Helmut Deissler, Raymonda Varon-Mateeva, Dorothea Gadzicki, Sabine Preisler-Adams, Dieter Niederacher, Simone Heidemann, Norbert Arnold, Nina Ditsch, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita K. Schmutzler, Ava Kwong, Orland Diez, Cecelia M. Dorfling, Elizabeth J. van Rensburg, Mary S. Beattie, Patricia A. Ganz, Soo Hwang Teo, Edith Olah, Christine S. Walsh, Beth Y. Karlan, Kunle O. Odunsi, Paul P.D. Pharoah, Simon A. Gayther, Joan Brunet, Lidia Feliubadalo, Ignacio Blanco, Conxi Lazaro, Ramunas Janavicius, Claudine Isaacs, Evgeny N. Imyanitov, Simona Agata, Marco Montagna, Amanda Ewart-Toland, Katie Wakeley, John Boggess, Wendy S. Rubinstein, Jack Basil, Kelly Phillips, Marion Piedmonte, Mark E. Robson, Kara Sarrel, Sohela Shah, Joseph Vijai, Aðalgeir Arason, Finn C. Nielsen, Thomas V.O. Hansen, Anneliese Fink-Retter, Muy-Kheng M. Tea, Christine Rappaport, Christian F. Singer, David E. Goldgar, John L. Hopper, Melissa C. Southey, Alexander Miron, Esther M. John, Wendy K. Chung, MaryBeth Terry, Mary B. Daly, Saundra S. Buys, Carrie L. Snyder, Henry T. Lynch, Linda Akloul, Capucine Delnatte, Isabelle Coupier, Pascal Pujol, Olivier Caron, Brigitte Bressac-de Paillerets, Nadia Boutry-Kryza, Mélanie Léoné, Sylvie Mazoyer, François Cornelis, Laurent Castera, Marion Fassy-Colcombet, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Betsy Bove, Lucy E. Side, M. John Kennedy, Mary E. Porteous, Lisa Walker, Patrick J. Morrison, Shirley V. Hodgson, Fiona Douglas, Carole Brewer, Joan Paterson, Jackie Cook, Trevor Cole, Diana M. Eccles, Rosemarie Davidson, Julian Adlard, Rosalind A. Eeles, Chris Jacobs, D. Gareth Evans, Elena Fineberg, Radka Platte, Steve D. Ellis, Debra Frost, Susan Peock, Margreet G.E.M. Ausems, Rogier A. Oldenburg, Maartje J. Hooning, Marleen Kets, Marinus J. Blok, Juul Wijnen, Hanne E.J. Meijers-Heijboer, Flora E. van Leeuwen, Theo A. van Os, Frans B.L. Hogervorst, Ute Hamann, Javier Benitez, María Isabel Tejada, Mercedes Durán, Ana Osorio, Bohdan Górski, Cezary Cybulski, Jacek Gronwald, Tomasz Byrski, Tomasz Huzarski, Elżbieta Złowocka, Katarzyna Durda, Katarzyna Jaworska, Jan Lubinski, Ania Jakubowska, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Per Karlsson, Hans Ehrencrona, Maria Soller, Niklas Loman, Gisela Barbany-Bustinza, Anna von Wachenfeldt, Maria A. Caligo, Torben A. Kruse, Anne-Bine Skytte, Uffe Birk Jensen, Anne-Marie Gerdes, Mads Thomassen, Anna Marie Mulligan, Hilmi Ozcelik, Irene L. Andrulis, Olga M. Sinilnikova, Sue Healey, Andrew Lee, Daniel Barrowdale, Lesley McGuffog, Tomas Kirchhoff, Xianshu Wang, Xiaoqing Chen, Jonathan Beesley, Penny Soucy, Karoline B. Kuchenbaecker, Susan J. Ramus, Antonis C. Antoniou, Mia M. Gaudet, and Fergus J. Couch
Abstract: Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.
Published: 2023
Full Text: View/download PDF

6. Data from MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma

Author: Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Graeme Eisenhofer, Giuseppe Opocher, Patricia L. M. Dahia, Massimo Mannelli, Karel Pacak, Felix Beuschlein, Miguel Urioste, Carli M.J. Tops, Henri J.L.M. Timmers, Elisa Taschin, Carlos Suarez, Alexander P.A. Stegmann, Frank Schillo, Macarena Ruiz-Ferrer, Giovanna Roncador, Nicole Reisch, Victoria Raymond, Elena Rapizzi, Nan Qin, Miguel Quesada-Charneco, Tamara Prodanov, Pierre-François Plouin, Peggy Pierre, Arnaud Murat, Luigi Mori, Anna Merlo, Arjen R. Mensenkamp, Rocío Letón, Jacques W.M. Lenders, Esther Korpershoek, Emiliano Honrado, Frederik J. Hes, Isabelle Guilhem, Álvaro Gómez-Graña, Encarna B. Gómez-García, Xavier Girerd, Tonino Ercolino, Ronald R. de Krijger, Mara Giacchè, Eleonora P.M. Corssmit, María-Dolores Chiara, Philippe Chanson, Maurizio Castellano, Salud Borrego, Sara Bobisse, Marinus J. Blok, Yves-Jean Bignon, Jérôme Bertherat, Sandra Bernaldo de Quirós, Marta Barontini, Laurence Amar, Aguirre A. de Cubas, Lucía Inglada-Pérez, Nasséra Abermil, Iñaki Comino-Méndez, Nicole Paes Morales, Francesca Schiavi, Alberto Cascón, and Nelly Burnichon
Abstract: Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL.Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics.Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine.Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828–37. ©2012 AACR.
Published: 2023
Full Text: View/download PDF

7. Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Author: Douglas F. Easton, Georgia Chenevix-Trench, Radka Platte, Xiaoqing Chen, Helene Holland, Amanda B. Spurdle, Jacques Simard, Heli Nevanlinna, Kristiina Aittomäki, Miguel de la Hoya, Trinidad Caldes, Ines Schönbuchner, Karin Kast, Sabine Preisler-Adams, Dorothea Gadzicki, Helmut Deissler, Christian Sutter, Dieter Niederacher, Raymonda Varon-Mateeva, Simone Heidemann, Norbert Arnold, Magdalena Lochmann, Alfons Meindl, Christoph Engel, Barbara Wappenschmidt, Rita Schmutzler, Jenny Gross, Beth Y. Karlan, Lara Sucheston, Susan J. Ramus, Conxi Lazaro, Ignacio Blanco, Laima Tihomirova, Evgeny Imyanitov, Cinzia Casella, Marco Montagna, Amanda Ewart Toland, Stephanie V. Blank, Peter E. Schwartz, Jack Basil, John F. Boggess, Katie Wakeley, Gustavo C. Rodriguez, Marion Piedmonte, Ana Dutra-Clarke, Vincent Devlin, Kenneth Offit, Tomas Kirchhoff, Bjarni A. Agnarsson, Lars Jønson, Thomas V.O. Hansen, Georg Pfeiler, Daphne Gschwantler-Kaulich, Anne Catharina Dressler, Christian F. Singer, David Goldgar, Alexander Miron, Yosuf Yassin, Saundra S. Buys, Esther M. John, Mary B. Terry, Mary B. Daly, John L. Hopper, Laurence Vénat-Bouvet, Marc Frénay, Catherine Nogues, Etienne Rouleau, Hagay Sobol, Tetsuro Noguchi, Catherine Loustalot, Laurence Faivre, Pascaline Berthet, Agnès Hardouin, Dominique Leroux, Hélène Dreyfus, Christine Lasset, Valérie Bonadona, Sylvie Mazoyer, Antoine de Pauw, Dominique Stoppa-Lyonnet, Andrew K. Godwin, Susan Peock, Huw Dorkins, M. John Kennedy, Lisa Walker, Mary E. Porteous, Patrick J. Morrison, Shirley Hodgson, Joan Paterson, Jackie Cook, Trevor Cole, Rosemarie Davidson, Gabriella Pichert, Fiona Lalloo, D. Gareth Evans, Don Conroy, Debra Frost, Clare Oliver, Margaret Cook, Matti Rookus, Frans Hogervorst, Cora M. Aalfs, Marinus J. Blok, E.J. Meijers-Heijboer, Peter Devilee, Christi J. van Asperen, Rob B. van der Luijt, Nicoline Hoogerbrugge, Mieke Kriege, Ute Hamann, Javier Benitez, Javier Godino, Maria-Isabel Tejada, Mercedes Durán, Adriana Lasa, Ana Osorio, Tomasz Huzarski, Jan Lubinski, Ania Jakubowska, Susan Domchek, Kate Nathanson, Beatrice Melin, Marie Stenmark-Askmalm, Johanna Rantala, Annika Lindblom, Helena Jernström, Ake Borg, Shimrit Cohen, Maya Dubrovsky, Roni Milgrom, Yael Laitman, Bella Kaufman, Eitan Friedman, Maria Caligo, Uffe Birk Jensen, Dorthe Cruger, Lone Sunde, Anne-Marie Gerdes, Mads Thomassen, Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon, Flavio Lejbkowicz, Gad Rennert, Mark H. Greene, Phuong L. Mai, Lenka Foretova, Bruce Poppe, Kathleen Claes, Michal Zikan, Csilla I. Szabo, Paolo Peterlongo, Valentina Dall'Olio, Anna Allavena, Alessandra Viel, Monica Barile, Daniela Zaffaroni, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Vernon S. Pankratz, Noralane M. Lindor, Xianshu Wang, Fergus J. Couch, Olufunmilayo I. Olopade, Gail Tomlinson, Patricia A. Ganz, Claudine Isaacs, Henry T. Lynch, Jeffrey N. Weitzel, Timothy R. Rebbeck, Yuan Chun Ding, Susan L. Neuhausen, Sue Healey, Olga M. Sinilnikova, Lesley McGuffog, Jonathan Beesley, and Antonis C. Antoniou
Abstract: Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction
Published: 2023
Full Text: View/download PDF

8. STS pathogenic variants in a Dutch patient cohort clinically suspected for X-linked ichthyosis show genetic heterogeneity

Author: Ivo F. Nagtzaam, Frank S. van Leersum, Laurie C.M. Kouwenberg, Marinus J. Blok, Maaike Vreeburg, Peter M. Steijlen, Antoni Gostyński, Michel van Geel, Dermatologie, MUMC+: MA AIOS Dermatologie (6), MUMC+: MA Dermatologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, MUMC+: MA AIOS Dermatologie (9), MUMC+: DA KG Lab Specialisten (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA KG Polikliniek (9), and MUMC+: MA Dermatologie (3)
Subjects: Cohort Studies, DEFICIENCY, Genetic Heterogeneity, Ichthyosis, X-Linked, Humans, Steryl-Sulfatase, Dermatology
Published: 2022
Full Text: View/download PDF

9. Generation and initial characterization of novel tumour organoid models to study human pancreatic cancer‐induced cachexia

Author: Marinus J. Blok, Steven W.M. Olde Damink, Rianne D. W. Vaes, Sander S. Rensen, Merel R. Aberle, David P J van Dijk, Lara R. Heij, Sylvia F Boj, Tessa T.J. Welbers, Surgery, RS: NUTRIM - R2 - Liver and digestive health, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: MA Heelkunde (9)
Subjects: 0301 basic medicine, Male, Cachexia, WEIGHT-LOSS, PROGRESSION, BIOBANK, Malignancy, medicine.disease_cause, DISEASE, CULTURE, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Pancreatic cancer, medicine, Organoid, Humans, Orthopedics and Sports Medicine, Interleukin 6, Aged, MONONUCLEAR-CELLS, RELEASE, Aged, 80 and over, biology, Hand Strength, business.industry, LIF, Interleukin-6, Cancer cachexia, Original Articles, Middle Aged, medicine.disease, Transplantation, Organoids, Pancreatic Neoplasms, 030104 developmental biology, GDF15, 030220 oncology & carcinogenesis, ESTABLISHMENT, Cancer research, biology.protein, Original Article, Female, KRAS, business
Abstract: Background The majority of patients with pancreatic cancer develops cachexia. The mechanisms underlying cancer cachexia development and progression remain elusive, although tumour‐derived factors are considered to play a major role. Pancreatic tumour organoids are in vitro three‐dimensional organ‐like structures that retain many pathophysiological characteristics of the in vivo tumour. We aimed to establish a pancreatic tumour organoid biobank from well‐phenotyped cachectic and non‐cachectic patients to enable identification of tumour‐derived factors driving cancer cachexia. Methods Organoids were generated from tumour tissue of eight pancreatic cancer patients. A comprehensive pre‐operative patient assessment of cachexia‐related parameters including nutritional status, physical performance, body composition, and inflammation was performed. Tumour‐related and cachexia‐related characteristics of the organoids were analysed using histological stainings, targeted sequencing, and real‐time–quantitative PCR. Cachexia‐related factors present in the circulation of the patients and in the tumour organoid secretome were analysed by enzyme‐linked immunosorbent assay. Results The established human pancreatic tumour organoids presented typical features of malignancy corresponding to the primary tumour (i.e. nuclear enlargement, multiple nucleoli, mitosis, apoptosis, and mutated KRAS and/or TP53). These tumour organoids also expressed variable levels of many known cachexia‐related genes including interleukin‐6 (IL‐6), TNF‐α, IL‐8, IL‐1α, IL‐1β, Mcp‐1, GDF15, and LIF. mRNA expression of IL‐1α and IL‐1β was significantly reduced in organoids from cachectic vs. non‐cachectic patients (IL‐1α: −3.8‐fold, P = 0.009, and IL‐1β: −4.7‐fold, P = 0.004). LIF, IL‐8, and GDF15 mRNA expression levels were significantly higher in organoids from cachectic vs. non‐cachectic patients (LIF: 1.6‐fold, P = 0.003; IL‐8: 1.4‐fold, P = 0.01; GDF15: 2.3‐fold, P
Published: 2020

10. Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

Author: Jenneke van den Ende, Encarna Gomez Garcia, Marianna Borecka, Marinus J. Blok, Marketa Safarikova, Robin de Putter, Mattias Van Heetvelde, Sabine Tejpar, Bruce Poppe, Marta Kalousová, Bettina Blaumeiser, Bram Parton, Jan Kral, Greet Wieme, Kathleen Claes, Michal Vocka, Zdenek Kleibl, Jana Soukupova, Petr Nehasil, Marketa Janatova, Petra Zemankova, Kim De Leeneer, Petra Kleiblova, Karen Geboes, Toon Rosseel, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: Oncology, medicine.medical_specialty, Cancer Research, Family Cancer History, Cancer-Predisposing Gene, endocrine system diseases, Colorectal cancer, overall survival, pancreatic ductal adenocarcinoma, MUTATION PREVALENCE, germline, Germline, Article, multigene panel testing, Pancreatic cancer, Internal medicine, medicine, Medicine and Health Sciences, Family history, CHEK2, RC254-282, RISK, family history, Science & Technology, business.industry, Melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ASSOCIATION, medicine.disease, BRCA1, digestive system diseases, SURVIVAL, Human medicine, business, Life Sciences & Biomedicine
Abstract: (1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38, 32%), (ii) relatives with PDAC (15/56, 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86, 17%) but more rare in sporadic PDAC (5/149, 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51, 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.
Published: 2021
Full Text: View/download PDF

11. Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

Author: Ana Osorio, Marinus J. Blok, Douglas F. Easton, Mary B. Daly, Nadine Andrieu, Michael Friedlander, Roger L. Milne, Brita Arver, Anne-Marie Gerdes, Olivier Caron, Katie Snape, D. Gareth Evans, Jacques Simard, David E. Goldgar, Anna Jakubowska, Edith Olah, Hongyan Li, Karin Kast, Dominique Stoppa-Lyonnet, Yen Y. Tan, Håkan Olsson, Lisa Walker, Trinidad Caldés, Véronique Mari, Catherine Noguès, Mary Porteous, Louise Izatt, Christoph Engel, Irene L. Andrulis, Rita K. Schmutzler, Hanne Meijers-Heijboer, Daniel Barrowdale, Johan J.P. Gille, Marc Tischkowitz, John L. Hopper, Marie Jose Roos-Blom, Matti A. Rookus, Mary Beth Terry, Marie Navratilova, Nicoline Hoogerbrugge, Lucy Side, Christine Lasset, T.M. Mooij, Christian F. Singer, Saundra S. Buys, Flora E. van Leeuwen, Sue-Anne McLachlan, Pascaline Berthet, Mark T. Rogers, Carole Brewer, Antonis C. Antoniou, Kelly-Anne Phillips, Lenka Foretova, Debra Frost, Esther M. John, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), APH - Quality of Care, APH - Methodology, Graduate School, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and CCA - Cancer Treatment and quality of life
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, life-style, PROGNOSIS, endocrine system diseases, Epidemiology, Population, SUSCEPTIBILITY, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine, ovarian, education, Prospective cohort study, skin and connective tissue diseases, education.field_of_study, business.industry, Proportional hazards model, BRCA mutation, Retrospective cohort study, medicine.disease, 3. Good health, KCONFAB, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Mutation (genetic algorithm), business
Abstract: Background: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. Methods: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. Results: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02–1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99–1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01–1.55 and HRP = 1.30; 95% CI, 0.83–2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. Conclusions: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. Impact: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.
Published: 2020
Full Text: View/download PDF

12. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Author: Ignacio Blanco, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, Núria Bonifaci, Lesley McGuffog, Vernon S Pankratz, Abul Islam, Francesca Mateo, Antoni Berenguer, Anna Petit, Isabel Català, Joan Brunet, Lidia Feliubadaló, Eva Tornero, Javier Benítez, Ana Osorio, Teresa Ramón y Cajal, Heli Nevanlinna, Kristiina Aittomäki, Banu K Arun, Amanda E Toland, Beth Y Karlan, Christine Walsh, Jenny Lester, Mark H Greene, Phuong L Mai, Robert L Nussbaum, Irene L Andrulis, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Rosa B Barkardottir, Anna Jakubowska, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Kathleen Claes, Tom Van Maerken, Orland Díez, Thomas V Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Miguel de la Hoya, Trinidad Caldés, Alison M Dunning, Clare Oliver, Elena Fineberg, Margaret Cook, Susan Peock, Emma McCann, Alex Murray, Chris Jacobs, Gabriella Pichert, Fiona Lalloo, Carol Chu, Huw Dorkins, Joan Paterson, Kai-Ren Ong, Manuel R Teixeira, Teixeira, Frans B L Hogervorst, Annemarie H van der Hout, Caroline Seynaeve, Rob B van der Luijt, Marjolijn J L Ligtenberg, Peter Devilee, Juul T Wijnen, Matti A Rookus, Hanne E J Meijers-Heijboer, Marinus J Blok, Ans M W van den Ouweland, Cora M Aalfs, Gustavo C Rodriguez, Kelly-Anne A Phillips, Marion Piedmonte, Stacy R Nerenstone, Victoria L Bae-Jump, David M O'Malley, Elena S Ratner, Rita K Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg J Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Uffe Birk Jensen, Mads Thomassen, Torben A Kruse, Lenka Foretova, Paolo Peterlongo, Loris Bernard, Bernard Peissel, Giulietta Scuvera, Siranoush Manoukian, Paolo Radice, Laura Ottini, Marco Montagna, Simona Agata, Christine Maugard, Jacques Simard, Penny Soucy, Andreas Berger, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler-Kaulich, Muy-Kheng Tea, Georg Pfeiler, BCFR, Esther M John, Alex Miron, Susan L Neuhausen, Mary Beth Terry, Wendy K Chung, Mary B Daly, David E Goldgar, Ramunas Janavicius, Cecilia M Dorfling, Elisabeth J van Rensburg, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Andrew K Godwin, Edith Olah, Steven A Narod, Gad Rennert, Shani Shimon Paluch, Yael Laitman, Eitan Friedman, SWE-BRCA, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Niklas Loman, Evgeny N Imyanitov, Ute Hamann, kConFab Investigators, Amanda B Spurdle, Sue Healey, Jeffrey N Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, GEMO, Dominique Stoppa-Lyonnet, Melanie Léoné, Laure Barjhoux, Marion Fassy-Colcombet, Antoine de Pauw, Christine Lasset, Sandra Fert Ferrer, Laurent Castera, Pascaline Berthet, François Cornelis, Yves-Jean Bignon, Francesca Damiola, Sylvie Mazoyer, Olga M Sinilnikova, Christopher A Maxwell, Joseph Vijai, Mark Robson, Noah Kauff, Marina J Corines, Danylko Villano, Julie Cunningham, Adam Lee, Noralane Lindor, Conxi Lázaro, Douglas F Easton, Kenneth Offit, Georgia Chenevix-Trench, Fergus J Couch, Antonis C Antoniou, and Miguel Angel Pujana
Subjects: Medicine, Science
Abstract: While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
Published: 2015
Full Text: View/download PDF

13. Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes

Author: Ana Vega, Logan C. Walker, Demis Tserpelis, Rita D. Brandão, Tim De Meyer, Klaas Mensaert, Amanda B. Spurdle, Anders Kvist, Vanessa Lattimore, M.N. Xenakis, Irene López-Perolio, Marinus J. Blok, Orland Diez, Miguel de la Hoya, Sara Gutiérrez-Enríquez, RS: FSE MSP, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Genetica & Celbiologie, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: HEREDITARY BREAST, Cancer Research, endocrine system diseases, PREDICTION, inherited breast, targeted RNA‐seq, 0302 clinical medicine, lynch syndrome, skin and connective tissue diseases, Genetics, RISK, RAD51C, BRCA1 Protein, GERMLINE MUTATIONS, Lynch syndrome, 3. Good health, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, RNA splicing, Hereditary Breast and Ovarian Cancer Syndrome, Female, RNA Splicing, Biology, MLH1, inherited breast/ovarian cancer syndrome, OVARIAN-CANCER, CLASSIFICATION, Cancer Genetics and Epigenetics, 03 medical and health sciences, alternative splicing, targeted RNA-seq, BRCA1/2, Cell Line, Tumor, medicine, UNCLASSIFIED VARIANTS, Humans, Genetic Predisposition to Disease, ASSAYS, Gene, BRCA2 Protein, Sequence Analysis, RNA, Alternative splicing, Electrophoresis, Capillary, medicine.disease, BRCA1, Colorectal Neoplasms, Hereditary Nonpolyposis, MSH6, MSH2, Mutation, ovarian cancer syndrome
Abstract: A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep‐sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA‐seq approach was used to analyse the naturally‐occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non‐BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non‐targeted RNA‐seq approach. We also compared splicing events from lymphoblastoid cell‐lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA‐seq to detect pathogenic changes in RNA‐splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted‐RNA‐seq can be very useful to classify variants based on their putative pathogenic impact on splicing., What's new? Hereditary familial breast/ovarian cancer (HBOC) syndrome involves numerous pathogenic variants, including variants of uncertain clinical significance (VUS). A subset of VUS, however, is suspected to influence RNA splicing, leading to the expression of potentially pathological transcript isoforms. Here, using a targeted RNA‐seq approach, naturally occurring splice isoforms were described for BRCA1/2, RAD51C, RAD51D, and eight additional tumor‐suppressor genes that are associated with HBOC and Lynch syndrome. The targeted RNA‐seq approach also identified aberrant splicing events associated with the presence of BRCA1/2 genetic variants and successfully distinguished complete from incomplete splicing events, which is of major importance in determining pathogenicity.
Published: 2019
Full Text: View/download PDF

14. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020
Full Text: View/download PDF

15. Functional categorization of BRCA1 variants of uncertain clinical significance in homologous recombination repair complementation assays

Author: J. Margriet Collée, Annemarie H. van der Hout, Isabelle Vandernoot, Lodewyk F. A. Wessels, Fonnet E. Bleeker, Marco J. Koudijs, Hanneke van der Gulden, Jan C. Oosterwijk, Sara Seneca, Geneviève Michils, Marinus J. Blok, Peter Bouwman, Ingrid van der Heijden, Maaike P.G. Vreeswijk, Ans M.W. van den Ouweland, Pascale Hilbert, Setareh Moghadasi, Katrien Storm, Bettina Blaumeiser, Merel E. Braspenning, Arjen R. Mensenkamp, Rob B. van der Luijt, Kathleen Claes, Nienke van der Stoep, Roebi de Bruijn, Frans B. L. Hogervorst, Karin Segers, Jos Jonkers, Cindy Badoer, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: 0301 basic medicine, Cancer Research, Genetic counseling, Mutagenesis (molecular biology technique), INTEGRATED EVALUATION, Biology, GUIDELINES, medicine.disease_cause, OVARIAN-CANCER, CLASSIFICATION, Olaparib, DIRECTED REPAIR, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, SEQUENCE VARIANTS, medicine, BREAST-CANCER, Missense mutation, Direct repeat, Clinical significance, Genetics, Mutation, MUTATIONS, SPLICING ANALYSIS, MISSENSE VARIANTS, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Homologous recombination
Abstract: Purpose: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway. Experimental Design: Two hundred thirty-eight BRCA1 VUS—comprising most BRCA1 VUS known in the Netherlands and Belgium—were tested for their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families. Results: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%–100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 12 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants. Conclusions: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.
Published: 2020

16. Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data

Author: Bart Charbon, Ivo F.A.C. Fokkema, Ronald H. Lekanne Deprez, Jeroen F.J. Laros, Claudia A. L. Ruivenkamp, Bart de Koning, Richard J. Sinke, Morris A. Swertz, Gert Thijs, Quinten Waisfisz, Nienke Wieskamp, Rolph Pfundt, Marielle E. van Gijn, Johan T. den Dunnen, Isaac J. Nijman, Kristin M. Abbott, R. Moritz, Mariska Slofstra, Jasper J. Saris, Rubayte Rahman, Kasper Joeri van der Velde, Marinus J. Blok, Maartje J Vogel, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Clinical Genetics, ACS - Pulmonary hypertension & thrombosis, Human Genetics, Amsterdam Reproduction & Development (AR&D), and Human genetics
Subjects: data sharing, Guidelines as Topic, Biology, Dna variants, computer.software_genre, Genome, RECOMMENDATIONS, CLASSIFICATION, 03 medical and health sciences, Databases, All institutes and research themes of the Radboud University Medical Center, Databases, Genetic, Genetics, SEQUENCE VARIANTS, diagnostics, Humans, Genetics(clinical), whole-exome sequencing, Genetics (clinical), Exome sequencing, database, 030304 developmental biology, Netherlands, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Information Dissemination, CARDIOMYOPATHIES, 030305 genetics & heredity, Genetic Diseases, Inborn, Data interpretation, Genetic Variation, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Pathogenicity, Penetrance, 3. Good health, Data Accuracy, Data sharing, Data quality, NGS, whole‐exome sequencing, Artificial intelligence, business, Laboratories, computer, Natural language processing
Abstract: Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next‐generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5‐tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as “consensus” when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled “conflicting”, while other nonconsensus observations were labeled “no consensus”. We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5‐tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.
Published: 2019
Full Text: View/download PDF

17. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Author: Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, PHENOTYPE, INCREASE, Prostate cancer, 0302 clinical medicine, Risk Factors, Young adult, skin and connective tissue diseases, Aged, 80 and over, Prostate cancer risk, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESSENGER-RNA DECAY, BRCA1 Protein, Genomics, GERMLINE MUTATIONS, Middle Aged, Prognosis, OVARIAN, CARRIERS, 3. Good health, 030220 oncology & carcinogenesis, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Tumor suppressor gene, Urology, Association (object-oriented programming), 3122 Cancers, MEDLINE, Article, Young Adult, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation, Journal Article, Genetic predisposition, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Risk factor, Genetic Association Studies, Aged, BRCA2 Protein, IDENTIFICATION, business.industry, Prostatic Neoplasms, medicine.disease, GENE, Confidence interval, APC, 030104 developmental biology, Mutation, 3111 Biomedicine, business
Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
Published: 2020
Full Text: View/download PDF

18. Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers

Author: A Inge-Marie Obdeijn, Matti A. Rookus, Jakob de Vries, Hester S. A. Oldenburg, Bernadette A M Heemskerk-Gerritsen, Linetta B. Koppert, C. Marleen Kets, Margriet Collée, Agnes Jager, Maartje J. Hooning, Peter Devilee, Marinus J. Blok, Caroline Seynaeve, Klaartje van Engelen, Denise J Jenner, Margreet G. E. M. Ausems, Hanne Meijers-Heijboer, Christi J. van Asperen, Academic Medical Center, ARD - Amsterdam Reproduction and Development, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, CCA - Cancer Treatment and quality of life, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Medical Oncology, Surgery, Radiology & Nuclear Medicine, and Clinical Genetics
Subjects: 0301 basic medicine, Cancer Research, Survival, Epidemiology, SURGERY, medicine.medical_treatment, FAMILIES, 0302 clinical medicine, Public Health Surveillance, CONTRALATERAL BREAST-CANCER, skin and connective tissue diseases, Mastectomy, Netherlands, Surveillance, BRCA1 Protein, Mortality rate, Hazard ratio, PROPHYLACTIC MASTECTOMY, WOMEN, Prognosis, SERIES, 3. Good health, TIME, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Oncology, 030220 oncology & carcinogenesis, Bilateral risk-reducing mastectomy, Mutation (genetic algorithm), Female, Cohort study, medicine.medical_specialty, Heterozygote, STRATEGIES, Breast Neoplasms, OVARIAN-CANCER, 03 medical and health sciences, Breast cancer, All institutes and research themes of the Radboud University Medical Center, BRCA1/2, Internal medicine, medicine, Humans, Mortality, Germ-Line Mutation, BRCA2 Protein, Proportional hazards model, business.industry, Prevention, BRCA mutation, medicine.disease, BRCA1, EFFICACY, 030104 developmental biology, Mutation, business, Risk Reduction Behavior
Abstract: Background In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. Methods In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. Results During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20–0.90) for overall mortality and 0.06 (95% CI 0.01–0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15–1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. Conclusion BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type. Electronic supplementary material The online version of this article (10.1007/s10549-019-05345-2) contains supplementary material, which is available to authorized users.
Published: 2019
Full Text: View/download PDF

19. Association of Genomic Domains in

Author: Vivek L, Patel, Evan L, Busch, Tara M, Friebel, Angel, Cronin, Goska, Leslie, Lesley, McGuffog, Julian, Adlard, Simona, Agata, Bjarni A, Agnarsson, Munaza, Ahmed, Kristiina, Aittomäki, Elisa, Alducci, Irene L, Andrulis, Adalgeir, Arason, Norbert, Arnold, Grazia, Artioli, Brita, Arver, Bernd, Auber, Jacopo, Azzollini, Judith, Balmaña, Rosa B, Barkardottir, Daniel R, Barnes, Alicia, Barroso, Daniel, Barrowdale, Muriel, Belotti, Javier, Benitez, Birgitte, Bertelsen, Marinus J, Blok, Istvan, Bodrogi, Valérie, Bonadona, Bernardo, Bonanni, Davide, Bondavalli, Susanne E, Boonen, Julika, Borde, Ake, Borg, Angela R, Bradbury, Angela, Brady, Carole, Brewer, Joan, Brunet, Bruno, Buecher, Saundra S, Buys, Santiago, Cabezas-Camarero, Trinidad, Caldés, Almuth, Caliebe, Maria A, Caligo, Mariarosaria, Calvello, Ian G, Campbell, Ileana, Carnevali, Estela, Carrasco, Tsun L, Chan, Annie T W, Chu, Wendy K, Chung, Kathleen B M, Claes, Gemo Study, Collaborators, Embrace, Collaborators, Jackie, Cook, Laura, Cortesi, Fergus J, Couch, Mary B, Daly, Giuseppe, Damante, Esther, Darder, Rosemarie, Davidson, Miguel, de la Hoya, Lara Della, Puppa, Joe, Dennis, Orland, Díez, Yuan Chun, Ding, Nina, Ditsch, Susan M, Domchek, Alan, Donaldson, Bernd, Dworniczak, Douglas F, Easton, Diana M, Eccles, Rosalind A, Eeles, Hans, Ehrencrona, Bent, Ejlertsen, Christoph, Engel, D Gareth, Evans, Laurence, Faivre, Ulrike, Faust, Lídia, Feliubadaló, Lenka, Foretova, Florentia, Fostira, George, Fountzilas, Debra, Frost, Vanesa, García-Barberán, Pilar, Garre, Marion, Gauthier-Villars, Lajos, Géczi, Andrea, Gehrig, Anne-Marie, Gerdes, Paul, Gesta, Giuseppe, Giannini, Gord, Glendon, Andrew K, Godwin, David E, Goldgar, Mark H, Greene, Angelica M, Gutierrez-Barrera, Eric, Hahnen, Ute, Hamann, Jan, Hauke, Natalie, Herold, Frans B L, Hogervorst, Ellen, Honisch, John L, Hopper, Peter J, Hulick, KConFab, Investigators, Hebon, Investigators, Louise, Izatt, Agnes, Jager, Paul, James, Ramunas, Janavicius, Uffe Birk, Jensen, Thomas Dyrso, Jensen, Oskar Th, Johannsson, Esther M, John, Vijai, Joseph, Eunyoung, Kang, Karin, Kast, Johanna I, Kiiski, Sung-Won, Kim, Zisun, Kim, Kwang-Pil, Ko, Irene, Konstantopoulou, Gero, Kramer, Lotte, Krogh, Torben A, Kruse, Ava, Kwong, Mirjam, Larsen, Christine, Lasset, Charlotte, Lautrup, Conxi, Lazaro, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lee, Johannes, Lemke, Fabienne, Lesueur, Annelie, Liljegren, Annika, Lindblom, Patricia, Llovet, Adria, Lopez-Fernández, Irene, Lopez-Perolio, Victor, Lorca, Jennifer T, Loud, Edmond S K, Ma, Phuong L, Mai, Siranoush, Manoukian, Veronique, Mari, Lynn, Martin, Laura, Matricardi, Noura, Mebirouk, Veronica, Medici, Hanne E J, Meijers-Heijboer, Alfons, Meindl, Arjen R, Mensenkamp, Clare, Miller, Denise Molina, Gomes, Marco, Montagna, Thea M, Mooij, Lidia, Moserle, Emmanuelle, Mouret-Fourme, Anna Marie, Mulligan, Katherine L, Nathanson, Marie, Navratilova, Heli, Nevanlinna, Dieter, Niederacher, Finn C Cilius, Nielsen, Liene, Nikitina-Zake, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Kai-Ren, Ong, Ana, Osorio, Claus-Eric, Ott, Domenico, Palli, Sue K, Park, Michael T, Parsons, Inge Sokilde, Pedersen, Bernard, Peissel, Ana, Peixoto, Pedro, Pérez-Segura, Paolo, Peterlongo, Annabeth Høgh, Petersen, Mary E, Porteous, Miguel Angel, Pujana, Paolo, Radice, Juliane, Ramser, Johanna, Rantala, Muhammad U, Rashid, Kerstin, Rhiem, Piera, Rizzolo, Mark E, Robson, Matti A, Rookus, Caroline M, Rossing, Kathryn J, Ruddy, Catarina, Santos, Claire, Saule, Rosa, Scarpitta, Rita K, Schmutzler, Hélène, Schuster, Leigha, Senter, Caroline M, Seynaeve, Payal D, Shah, Priyanka, Sharma, Vivian Y, Shin, Valentina, Silvestri, Jacques, Simard, Christian F, Singer, Anne-Bine, Skytte, Katie, Snape, Angela R, Solano, Penny, Soucy, Melissa C, Southey, Amanda B, Spurdle, Linda, Steele, Doris, Steinemann, Dominique, Stoppa-Lyonnet, Agostina, Stradella, Lone, Sunde, Christian, Sutter, Yen Y, Tan, Manuel R, Teixeira, Soo Hwang, Teo, Mads, Thomassen, Maria Grazia, Tibiletti, Marc, Tischkowitz, Silvia, Tognazzo, Amanda E, Toland, Stefania, Tommasi, Diana, Torres, Angela, Toss, Alison H, Trainer, Nadine, Tung, Christi J, van Asperen, Frederieke H, van der Baan, Lizet E, van der Kolk, Rob B, van der Luijt, Liselotte P, van Hest, Liliana, Varesco, Raymonda, Varon-Mateeva, Alessandra, Viel, Jeroen, Vierstraete, Roberta, Villa, Anna, von Wachenfeldt, Philipp, Wagner, Shan, Wang-Gohrke, Barbara, Wappenschmidt, Jeffrey N, Weitzel, Greet, Wieme, Siddhartha, Yadav, Drakoulis, Yannoukakos, Sook-Yee, Yoon, Cristina, Zanzottera, Kristin K, Zorn, Anthony V, D'Amico, Matthew L, Freedman, Mark M, Pomerantz, Georgia, Chenevix-Trench, Antonis C, Antoniou, Susan L, Neuhausen, Laura, Ottini, Henriette Roed, Nielsen, and Timothy R, Rebbeck
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, Adolescent, BRCA1 Protein, Prostatic Neoplasms, Genomics, Middle Aged, Prognosis, Young Adult, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, Genetic Association Studies, Aged
Abstract: Pathogenic sequence variants (PSV) in
Published: 2019

20. Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for

Author: Hongyan, Li, Mary Beth, Terry, Antonis C, Antoniou, Kelly-Anne, Phillips, Karin, Kast, Thea M, Mooij, Christoph, Engel, Catherine, Noguès, Dominique, Stoppa-Lyonnet, Christine, Lasset, Pascaline, Berthet, Veronique, Mari, Olivier, Caron, Daniel, Barrowdale, Debra, Frost, Carole, Brewer, D Gareth, Evans, Louise, Izatt, Lucy, Side, Lisa, Walker, Marc, Tischkowitz, Mark T, Rogers, Mary E, Porteous, Katie, Snape, Hanne E J, Meijers-Heijboer, Johan J P, Gille, Marinus J, Blok, Nicoline, Hoogerbrugge, Mary B, Daly, Irene L, Andrulis, Saundra S, Buys, Esther M, John, Sue-Anne, McLachlan, Michael, Friedlander, Yen Y, Tan, Ana, Osorio, Trinidad, Caldes, Anna, Jakubowska, Jacques, Simard, Christian F, Singer, Edith, Olah, Marie, Navratilova, Lenka, Foretova, Anne-Marie, Gerdes, Marie-José, Roos-Blom, Brita, Arver, Håkan, Olsson, Rita K, Schmutzler, John L, Hopper, Roger L, Milne, Douglas F, Easton, Flora E, Van Leeuwen, Matti A, Rookus, Nadine, Andrieu, and David E, Goldgar
Subjects: Adult, BRCA2 Protein, Heterozygote, endocrine system diseases, Alcohol Drinking, BRCA1 Protein, Breast Neoplasms, Middle Aged, Article, Cigarette Smoking, Risk Factors, Mutation, Humans, Female, Genetic Predisposition to Disease, Prospective Studies, skin and connective tissue diseases, Life Style, Reproductive History, Retrospective Studies
Abstract: BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer (BC), but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high BC risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with BC risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers; 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers; 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with BC risk, except smoking for more than five years before a first full-term pregnancy (FFTP) when compared to parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HR(R)) was 1.19 (95%CI:1.02,1.39) and the HR from prospective analysis (HR(P)) was 1.36 (95%CI:0.99,1.87). For BRCA2 mutation carriers, smoking for more than five years before a FFTP showed an association of a similar magnitude, but the confidence limits were wider (HR(R)=1.25,95%CI:1.01,1.55 and HR(P)=1.30,95%CI:0.83,2.01). For both carrier groups, alcohol consumption was not associated with BC risk. CONCLUSIONS: The finding that smoking during the pre-reproductive years increases BC risk for mutation carriers warrants further investigation.
Published: 2019

21. Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples

Author: Orland Diez, Mads Thomassen, Rita D. Brandão, Samantha C Ayoub, Phillip J. Whiley, Olufunmilayo I. Olopade, Mara Colombo, Claude Houdayer, Gorka Ruiz de Garibay, Diana Baralle, Conxi Lázaro, Kumar Lal, Paolo Radice, Demis Tserpelis, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Gemma Montalban, Logan C. Walker, Barbara Wappenschmidt, Michael T. Parsons, Ana Vega, Ana Blanco, Alexandra Becker, Marta Santamariña, Irene López-Perolio, Bifeng Zhang, Marinus J. Blok, Amanda B. Spurdle, James D. Fackenthal, kConFab Investigators, Giovanna De Vecchi, Toshio F. Yoshimatsu, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, and Genetica & Celbiologie
Subjects: 0301 basic medicine, medicine.medical_specialty, Breast Neoplasms, Biology, medicine.disease_cause, Germline, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Molecular genetics, Cell Line, Tumor, Genetics, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Genetic Testing, RNA, Messenger, Allele, skin and connective tissue diseases, Gene, Genetics (clinical), BRCA2 Protein, Ovarian Neoplasms, Mutation, BRCA1 Protein, Alternative splicing, Alternative Splicing, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, MCF-7 Cells, Female, RNA Splice Sites
Abstract: BACKGROUND: BRCA1 and BRCA2 are the two principal tumour suppressor genes associated with inherited high risk of breast and ovarian cancer. Genetic testing of BRCA1/2 will often reveal one or more sequence variants of uncertain clinical significance, some of which may affect normal splicing patterns and thereby disrupt gene function. mRNA analyses are therefore among the tests used to interpret the clinical significance of some genetic variants. However, these could be confounded by the appearance of naturally occurring alternative transcripts unrelated to germline sequence variation or defects in gene function. To understand which novel splicing events are associated with splicing mutations and which are part of the normal BRCA2 splicing repertoire, a study was undertaken by members of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium to characterise the spectrum of naturally occurring BRCA2 mRNA alternate-splicing events.METHODS: mRNA was prepared from several blood and breast tissue-derived cells and cell lines by contributing ENIGMA laboratories. cDNA representing BRCA2 alternate splice sites was amplified and visualised using capillary or agarose gel electrophoresis, followed by sequencing.RESULTS: We demonstrate the existence of 24 different BRCA2 mRNA alternate-splicing events in lymphoblastoid cell lines and both breast cancer and non-cancerous breast cell lines.CONCLUSIONS: These naturally occurring alternate-splicing events contribute to the array of cDNA fragments that may be seen in assays for mutation-associated splicing defects. Caution must be observed in assigning alternate-splicing events to potential splicing mutations.
Published: 2016
Full Text: View/download PDF

22. BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

Author: Eliseos J. Mucaki, Stacey L. Edwards, Marinus J. Blok, Jana Soukupova, Mariana Borecka, Marta Santamariña, Marketa Janatova, Paolo Peterlongo, Ana Vega, Ben C. Shirley, Amanda B. Spurdle, Peter K. Rogan, Gaetana Gambino, Phillip J. Whiley, Lenka Stolarova, Petra Zemankova, O. Diez, Siranoush Manoukian, Thomas van Overeem Hansen, David E. Goldgar, Bernardo Bonanni, Emma Tudini, Sara Gutiérrez-Enríquez, Leslie Burke, Elizabeth Santana dos Santos, Michael T. Parsons, Kathleen Claes, Jan Sevcik, Kim De Leeneer, Melissa A. Brown, Paolo Radice, Maria Caligo, Etienne Rouleau, Sandrine M. Caputo, Alejandro Moles-Fernández, Maria Rossing, Klara Lhotova, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: 0301 basic medicine, SUSCEPTIBILITY, Genome, Biochemistry, 0302 clinical medicine, Medicine and Health Sciences, TRANSCRIPTION, Age of Onset, Promoter Regions, Genetic, Research Articles, Genetics (clinical), GENE-EXPRESSION, Genetics, RISK, Tumor, BRCA1 Protein, BRCA1, BRCA2, breast cancer, promoter, transcription, variants of unknown clinical significance (VUS), 5' Untranslated Regions, BRCA2 Protein, Breast Neoplasms, CCAAT-Binding Factor, Cell Line, Tumor, Female, Genetic Predisposition to Disease, Humans, MCF-7 Cells, PAX5 Transcription Factor, Protein Binding, Germ-Line Mutation, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, Research Article, GERMLINE VARIANTS, REGULATORY ELEMENTS, Biology, DNA sequencing, OVARIAN-CANCER, Cell Line, Promoter Regions, 03 medical and health sciences, Breast cancer, Genetic, medicine, Clinical significance, Allele frequency, COMPLEX, MUTATIONS, Biology and Life Sciences, Promoter, medicine.disease, Minor allele frequency, 030104 developmental biology
Abstract: © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc. The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5′ noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.
Published: 2018

23. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Olufunmilayo I. Olopade, Darcy L. Thull, Raanan Berger, Mary Beth Terry, Michel Longy, Timothy R. Rebbeck, Gord Glendon, Min Hyuk Lee, Javier Benitez, Mark T. Rogers, Mark H. Greene, Dezheng Huo, Adalgeir Arason, Carole Brewer, Siranoush Manoukian, Jackie Cook, Louise Izatt, Yuan Chun Ding, Dieter Niederacher, Nadine Tung, Sophie Giraud, Henriette Roed Nielsen, Antonis C. Antoniou, Bernhard H. F. Weber, Bruno Buecher, Goska Leslie, Amanda E. Toland, Anna Marie Mulligan, Ane Y. Schmidt, Noralane M. Lindor, Véronique Mari, Tara M. Friebel, Cecilia M. Dorfling, Ugnius Mickys, Lenka Foretova, Andrew K. Godwin, Bernd Dworniczak, Tsun Leung Chan, Monica Barile, Angela R. Solano, Susan J. Ramus, Laurence Faivre, Susan L. Neuhausen, Ana Peixoto, Julio Abugattas, Mattias Van Heetvelde, Jacqueline Eason, Muhammad Usman Rashid, Barbara Pasini, Henrique de Campos Reis Galvão, Heli Nevanlinna, Lucy Side, Nina Peruga, Marco Montagna, Amie Blanco, Alison H. Trainer, Cristina Zanzottera, Arjen R. Mensenkamp, Douglas F. Easton, Inge Søkilde Pedersen, Kenneth Offit, Judy Garber, Sook-Yee Yoon, Uffe Birk Jensen, Irene Konstantopoulou, Barbara Wappenschmidt, Stefanie Engert, Robert L. Nussbaum, Kai-ren Ong, Ros Eeles, Marinus J. Blok, Yael Laitman, Alex Teulé, Marion Gauthier-Villars, Daniel Barrowdale, Mads Thomassen, Torben A Kruse, Hanne Meijers-Heijboer, Abigail Thomas, Susan M. Domchek, Jacques Simard, Jamal Zidan, Paul A. James, Rob B. van der Luijt, Nina Ditsch, Annette Lee, Joseph Vijai, Kathleen R. Blazer, Elizabeth J. van Rensburg, János Papp, Lizet E. van der Kolk, Eitan Friedman, Pascal Pujol, Johanna Rantala, Patricia A. Ganz, Esther M. John, Conxi Lázaro, Jacek Gronwald, Paul Gesta, Jan Hauke, Simona Agata, Leo Auerbach, Paolo Radice, Fabienne Prieur, Beth Y. Karlan, Antoine De Pauw, Paolo Peterlongo, Sandrine M. Caputo, Sue K. Park, Marc Tischkowitz, Jocelyne Chiquette, Karin Kast, Annemieke H. van der Hout, Eric Hahnen, Grzegorz Sukiennicki, Debra Frost, Noura Mebirouk, Angel Izquierdo, Alex Henderson, Carolina Velázquez, Raymonda Varon-Mateeva, J. Margriet Collée, Soo-Hwang Teo, Esther Pohl, Rosa B. Barkardottir, Rita K. Schmutzler, Kim De Leeneer, Andrea Gehrig, D. Gareth Evans, Jeffrey N. Weitzel, Katherine L. Nathanson, Lesley McGuffog, Christoph Engel, Amanda B. Spurdle, Austin Miller, Edith Olah, Hans Ehrencrona, Almuth Caliebe, Zoltan Matrai, Ian G. Campbell, Christina G. Selkirk, Kirsten B. Moysich, Ella Asseryanis, Wendy K. Chung, Michael T. Parsons, Shan Wang-Gohrke, Thomas P. Slavin, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Christian F. Singer, Lesley Andrews, Jacopo Azzollini, Peter J. Hulick, Judith Balmaña, Anne-Marie Gerdes, Frans B. L. Hogervorst, Capucine Delnatte, Miguel de la Hoya, Katarzyna Kaczmarek, Angelica M. Gutierrez-Barrera, Claudine Isaacs, Lisa Walker, Doris Steinemann, Huu Phuc Nguyen, Anna von Wachenfeldt, Saundra S. Buys, Fabienne Lesueur, Kristin K. Zorn, Kerstin Rhiem, Manuel R. Teixeira, Linda Steele, Ava Kwong, Alfons Meindl, Evgeny N. Imyanitov, Giuseppe Giannini, Banu Arun, Vilius Rudaitis, Norbert Arnold, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Jacob Korach, Ana Vega, Nisha Pradhan, David E. Goldgar, Anna Jakubowska, Angela R. Bradbury, Cora M. Aalfs, kConFab Investigators, Lídia Feliubadaló, Annelie Liljegren, Ana Osorio, Sabine Topka, Julia Hentschel, Katie Snape, Fergus J. Couch, Ute Hamann, Anna Öfverholm, Edenir Inêz Palmero, Jacob Musinsky, Adriana Lasa, Silvia Tognazzo, Payal D. Shah, Drakoulis Yannoukakos, Valérie Bonadona, Laura Papi, Georgia Chenevix-Trench, Christi J. van Asperen, Hagay Sobol, Kristiina Aittomäki, Cristina Martínez-Bouzas, Jan Lubinski, Csilla Szabo, Joanne Ngeow, Hebon, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Christian Sutter, Yen Y. Tan, Trinidad Caldés, Rosemarie Davidson, Jenny Lester, Andreas Berger, Mark E. Robson, Jennifer T. Loud, Cynthia Villarreal-Garza, Eva Machackova, Leigha Senter, Irene L. Andrulis, Sandra Fert Ferrer, Diana Torres, Sung-Won Kim, Karolina Prajzendanc, Christine Lasset, Embrace, Jeffrey M. Fowler, Bernardo Bonanni, Bent Ejlertsen, Liliana Varesco, Orland Diez, Kathleen Claes, Leslie, Goska [0000-0001-5756-6222], Easton, Douglas [0000-0003-2444-3247], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Centre Léon Bérard [Lyon], Institut Curie [Paris], CRLCC René Gauducheau, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Métropole Savoie [Chambéry], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Clinical Genetics, Human genetics, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Fundações de Amparo à Pesquisa (Brasil), Research Foundation - Flanders, University of Helsinki, Sigrid Juselius Foundation, Dutch Cancer Society, Netherlands Organization for Scientific Research, Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministero della Salute, Istituto Oncologico Veneto, University of Tasmania, Australian Cancer Research Foundation, Ministry of Health and Welfare (South Korea), Charles University (Czech Republic), National Research Foundation Singapore, Russian Foundation for Basic Research, Istituto Toscano Tumori, Israel Cancer Association USA, Swedish Cancer Society, Foundation for Women's Cancer, University of Pittsburgh, Cancer Australia, American Cancer Society, The Ohio State University, National Institutes of Health (US), Cancer Research UK, European Commission, Canadian Institutes of Health Research, Department of Trade and Industry (UK), Susan G. Komen Foundation, Breast Cancer Research Foundation, Genome Canada, National Cancer Institute (US), Research Council of Lithuania, Cancer Association of South Africa, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Sanidad y Política Social (España), Associazione Italiana per la Ricerca sul Cancro, Fondazione Italiana per la Ricerca sul Cancro, Ministero dell'Istruzione, dell'Università e della Ricerca, Institut Pasteur, Fondazione Cenci Bolognetti, Greek Government, Pontificia Universidad Javeriana, Royal Marsden NHS Foundation Trust, Kansas State University, Fundación Mutua Madrileña, Ligue Nationale contre le Cancer (France), Georgetown University, Human Genetics, Other departments, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, HEREDITARY BREAST, Mutation rate, Internationality, endocrine system diseases, Càncer d'ovari, Gene mutation, medicine.disease_cause, geography, Race (biology), 0302 clinical medicine, Breast cancer, FOUNDER MUTATIONS, Databases, Genetic, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], skin and connective tissue diseases, Genetics (clinical), Genetics, Mutation, medicine.diagnostic_test, Geography, RISK HISPANIC FAMILIES, BRCA1 Protein, 185DELAG MUTATION, GERMLINE MUTATIONS, 3. Good health, PROSTATE-CANCER, ovarian cancer, 030220 oncology & carcinogenesis, Medical genetics, ethnicity, BREAST-CANCER PATIENTS, BRCA1, BRCA2, breast cancer, mutation, medicine.medical_specialty, Biology, OVARIAN-CANCER, Article, Càncer de mama, BRCA2 Protein, Family, Humans, 03 medical and health sciences, Databases, Germline mutation, Genetic, Ovarian cancer, medicine, ddc:610, Genotyping, Genetic testing, PHENOTYPE ANALYSIS, BRCA1, BRCA2, Breast Cancer, HAPLOTYPE ANALYSIS, Mutació (Biologia), Mutation (Biology), 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018
Full Text: View/download PDF

24. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract: The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).
Published: 2017
Full Text: View/download PDF

25. FMR1 low sub-genotype does not rescue BRCA1/2-mutated human embryos and does not explain primary ovarian insufficiency among BRCA1/2-carriers

Author: Demis Tserpelis, Rita D. Brandão, K Van Roozendaal, Marinus J. Blok, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: Oncology, Male, medicine.medical_specialty, Heterozygote, endocrine system diseases, Genotype, Population, Genes, BRCA2, Genes, BRCA1, preimplantation genetic diagnostics, Biology, medicine.disease_cause, Oogenesis, Fragile X Mental Retardation Protein, Internal medicine, medicine, Humans, embryo rescue, skin and connective tissue diseases, education, FMR1, Genetic Association Studies, Preimplantation Diagnosis, Retrospective Studies, Genetics, education.field_of_study, Mutation, Rehabilitation, Obstetrics and Gynecology, Retrospective cohort study, BRCA2 Protein, Embryo, Mammalian, BRCA1, primary ovarian insufficiency, Reproductive Medicine, Medical genetics, Female
Abstract: STUDY QUESTION Can we confirm in our population whether FMRI low sub-genotypes are associated with BRCA1/2 mutations, as recently proposed? SUMMARY ANSWER Our results indicate that the distribution of the FMR1 sub-genotypes in female BRCA1/2-mutation carriers is significantly different from what has been reported previously and resembles that of the control population. FMRI low sub-genotypes are not associated with BRCA1/2 mutations and this association is also absent among male mutation carriers. WHAT IS KNOWN ALREADY Recently, BRCA1 mutations were reported to be associated with primary ovarian insufficiency (POI) in female carriers. In animal models, BRCA2-deficiency also results in impaired oogenesis. A recent study has reported that the POI in BRCA1/2-mutation carriers is most likely due to low FMR1 sub-genotype (CGG n < 26) and the authors also suggested that low sub-genotypes of the FMR1 gene might be important to rescue the BRCA1/2 embryos, which would otherwise be embryonically-lethal. STUDY DESIGN, SIZE, DURATION This retrospective study was performed in October and November of 2012, using genetic material of 464 patients who underwent genetic screening in our centre in the past. PARTICIPANTS/MATERIALS, SETTING, METHODS We tested the FMR1 sub-genotypes in 60 female and 29 males with either BRCA1 or BRCA2 mutations and 375 controls by PCR amplification and size fragment analysis. MAIN RESULTS We did not find any evidence for an association of FMR1 low sub-genotypes and BRCA1/2 mutations. LIMITATIONS, REASONS FOR CAUTION This association study assumes that the female BRCA1/2 population tested has POI. WIDER IMPLICATIONS OF THE FINDINGS Low FMR1 sub-genotypes are not responsible for the presumed rescue of embryos with BRCA1/2 mutations. Furthermore, the molecular mechanism of the POI in BRCA1/2-female carriers is not likely to be associated with low FMR1 sub-genotype. STUDY FUNDING/COMPETING INTEREST(S) The Department of Clinical Genetics of the Maastricht University Medical Centre supported the study. The authors do not have any competing interests to declare.
Published: 2013
Full Text: View/download PDF

26. PGD for hereditary breast and ovarian cancer: the route to universal tests for BRCA1 and BRCA2 mutation carriers

Author: Christine E. M. de Die-Smulders, Joep P. Geraedts, I.A.P. Derks-Smeets, Marinus J. Blok, Aimee D C Paulussen, Marion Drüsedau, Encarna B. Gomez-Garcia, Jos C. F. M. Dreesen, Hubert J T Smeets, Edith Coonen, Ron J. T. van Golde, P.M.M. Kastrop, Jannie van Echten-Arends, MUMC+: DA KG Lab Centraal Lab (9), Promovendi ODB, Genetica & Celbiologie, Obstetrie & Gynaecologie, MUMC+: VMK IVF Lab (9), MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), Klinische Genetica, and RS: GROW - School for Oncology and Reproduction
Subjects: ESHRE PGD, Adult, Male, medicine.medical_specialty, PREIMPLANTATION GENETIC DIAGNOSIS, medicine.medical_treatment, Breast Neoplasms, Prenatal diagnosis, Biology, Preimplantation genetic diagnosis, microsatellites, FAMILIES, DISEASE, Article, Intracytoplasmic sperm injection, EMBRYOS, Pregnancy, Prenatal Diagnosis, FERTILIZATION, Multiplex polymerase chain reaction, Genetics, medicine, Humans, skin and connective tissue diseases, Preimplantation Diagnosis, Genetics (clinical), PGD, BRCA2 Protein, Ovarian Neoplasms, Gynecology, HBOC, BRCA1 Protein, CONSORTIUM, Haplotype, WOMEN, INTRACYTOPLASMIC SPERM INJECTION, BRCA1, medicine.disease, BRCA2, Embryo transfer, Pedigree, PRACTICE GUIDELINES, Mutation, Female, Ovarian cancer, Microsatellite Repeats
Abstract: Preimplantation Genetic Diagnosis (PGD) is a method of testing in vitro embryos as an alternative to prenatal diagnosis with possible termination of pregnancy in case of an affected child. Recently, PGD for hereditary breast and ovarian cancer caused by BRCA1 and BRCA2 mutations has found its way in specialized labs. We describe the route to universal single-cell PGD tests for carriers of BRCA1/2 mutations. Originally, mutation-specific protocols with one or two markers were set up and changed when new couples were not informative. This route of changing protocols was finalized after 2 years with universal tests for both BRCA1 and BRCA2 mutation carriers based on haplotyping of, respectively, 6 (BRCA1) and 8 (BRCA2) microsatellite markers in a multiplex PCR. Using all protocols, 30 couples had a total of 47 PGD cycles performed. Eight cycles were cancelled upon IVF treatment due to hypostimulation. Of the remaining 39 cycles, a total of 261 embryos were biopsied and a genetic diagnosis was obtained in 244 (93%). In 34 of the 39 cycles (84.6%), an embryo transfer was possible and resulted in 8 pregnancies leading to a fetal heart beat per oocyte retrieval of 20.5% and a fetal heart beat per embryonic transfer of 23.5%. The preparation time and costs for set-up and validation of tests are minimized. The informativity of microsatellite markers used in the universal PGD-PCR tests is based on CEPH and deCODE pedigrees, making the tests applicable in 90% of couples coming from these populations.
Published: 2013
Full Text: View/download PDF

27. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

Author: Marcel R. Nelen, Aisha S. Sie, Michiel Simons, Marjolijn J. L. Ligtenberg, Encarna B. Gomez-Garcia, Johan Bulten, Alexander Hoischen, Hicham Ouchene, Marinus J. Blok, Nicoline Hoogerbrugge, Arjen R. Mensenkamp, Joanne A. de Hullu, Bastiaan B J Tops, Monique van Asseldonk, Robbert D.A. Weren, Astrid Eijkelenboom, MUMC+: DA KG Polikliniek (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: 0301 basic medicine, endocrine system diseases, DNA Mutational Analysis, Genes, BRCA2, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Genes, BRCA1, PREDICTS SENSITIVITY, Loss of Heterozygosity, POLY(ADP-RIBOSE) POLYMERASE, medicine.disease_cause, Molecular Inversion Probe, chemistry.chemical_compound, 0302 clinical medicine, Ovarian carcinoma, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Methods, Multiplex, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, Mutation, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], OLAPARIB, Disease Management, personalized medicine, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], ovarian cancer, 030220 oncology & carcinogenesis, MOLECULAR INVERSION PROBES, Female, single molecule molecular inversion probes, RISK-ASSESSMENT, PARP-inhibitor, DNA Copy Number Variations, Genotype, Clinical Decision-Making, cancer predisposition, Genetic Counseling, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Biology, BREAST, Olaparib, 03 medical and health sciences, GERMLINE, Genetics, medicine, Humans, Genetic Predisposition to Disease, Multiplex ligation-dependent probe amplification, Genetic Testing, Alleles, Genetic Association Studies, Germ-Line Mutation, business.industry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Reproducibility of Results, SOMATIC MUTATIONS, RANDOMIZED PHASE-2 TRIAL, medicine.disease, BRCA1, BRCA2, PARP‐inhibitor, BRCA testing, 030104 developmental biology, chemistry, Amino Acid Substitution, CANCER INCIDENCE, Cancer research, Personalized medicine, Ovarian cancer, business
Abstract: With the recent introduction of Poly(ADP‐ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin‐fixed, paraffin‐embedded (FFPE) tissue, we have developed a single‐molecule molecular inversion probe (smMIP)‐based targeted next‐generation sequencing (NGS) approach. Our smMIP‐based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin‐induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation‐negative results. Multiplex ligation‐dependent probe amplification (MLPA) and Methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.
Published: 2017

28. The

Author: Setareh, Moghadasi, Huong D, Meeks, Maaike Pg, Vreeswijk, Linda Am, Janssen, Åke, Borg, Hans, Ehrencrona, Ylva, Paulsson-Karlsson, Barbara, Wappenschmidt, Christoph, Engel, Andrea, Gehrig, Norbert, Arnold, Thomas Van Overeem, Hansen, Mads, Thomassen, Uffe Birk, Jensen, Torben A, Kruse, Bent, Ejlertsen, Anne-Marie, Gerdes, Inge Søkilde, Pedersen, Sandrine M, Caputo, Fergus, Couch, Emily J, Hallberg, Ans Mw, van den Ouweland, Margriet J, Collée, Erik, Teugels, Muriel A, Adank, Rob B, van der Luijt, Arjen R, Mensenkamp, Jan C, Oosterwijk, Marinus J, Blok, Nicolas, Janin, Kathleen Bm, Claes, Kathy, Tucker, Valeria, Viassolo, Amanda Ewart, Toland, Diana E, Eccles, Peter, Devilee, Christie J, Van Asperen, Amanda B, Spurdle, David E, Goldgar, and Encarna Gómez, García
Subjects: Ovarian Neoplasms, BRCA1 Protein, Risk Factors, Chromosome Segregation, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease
Abstract: We previously showed that theData were collected from 129In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).Our results confirm that
Published: 2017

29. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author: Marco Montagna, Bruno Buecher, Goska Leslie, Daniel Barrowdale, Anita Bane, Louise Izatt, Eitan Friedman, Yosr Hamdi, Kenneth Offit, Klaartje van Engelen, Soo Hwang Teo, Frans B. L. Hogervorst, Conxi Lázaro, Sylvie Mazoyer, Diana Eccles, Yuan Chun Ding, Laura Papi, Georgia Chenevix-Trench, Katarzyna Kaczmarek, Laima Tihomirova, Jacek Gronwald, Jocelyne Chiquette, Patricia A. Ganz, Thomas P. Slavin, Kathleen Claes, Paolo Radice, Elizabeth J. van Rensburg, Adalgeir Arason, Lenka Foretova, Milena Mariani, Johanna Rantala, Pascaline Berthet, Evgeny N. Imyanitov, Claudine Isaacs, Esther M. John, Maite Laurent, Irene L. Andrulis, Juul T. Wijnen, Paolo Peterlongo, Susan M. Domchek, Banu Arun, Amanda E. Toland, Anna Marie Mulligan, Penny Soucy, Kristiina Aittomäki, Orland Diez, Heli Nevanlinna, Anne-Marie Gerdes, Austin Miller, Olufunmilayo I. Olopade, Raymonda Varon-Mateeva, Alfons Meindl, Cecilia M. Dorfling, Niklas Loman, Paul A. James, Susan L. Neuhausen, Muy Kheng Tea, Inge Søkilde Pedersen, Arnaud Droit, D. Gareth Evans, Mark E. Robson, Jennifer T. Loud, Jan C. Oosterwijk, Judy Garber, Douglas F. Easton, Jacques Simard, Mark H. Greene, Pamela S. Ganschow, Edith Olah, Audrey Lemaçon, Norbert Arnold, Catherine M. Phelan, Gad Rennert, Judy Kirk, Johanna Sokolowska, Tomi Pastinen, Robert L. Nussbaum, Simon A. Gayther, Karoline B. Kuchenbaeker, Mads Thomassen, Ros Eeles, Riccardo Dolcetti, Hanne Meijers-Heijboer, Marc Tischkowitz, George Fountzilas, Laure Barjhoux, Kristie Bobolis, Christoph Engel, Bernardo Bonanni, Sue K. Park, Beth Y. Karlan, Nicolas Sevenet, Bent Ejlertsen, Wendy K. Chung, Timothy R. Rebbeck, Amanda B. Spurdle, Peter J. Hulick, Mary B. Daly, Yen Y. Tan, Annelie Liljegren, Carolien M. Kets, Miguel de la Hoya, Gord Glendon, Mieke Kriege, Rita K. Schmutzler, Manuel R. Teixeira, Christine Rappaport-Fuerhauser, Pedro Pérez Segura, William D. Foulkes, Rosemarie Davidson, Steven N. Hart, Javier Benitez, Jenny Lester, Melissa C. Southey, Ramunas Janavicius, Uffe Birk Jensen, Zakaria Einbeigi, Christian F. Singer, Jacopo Azzollini, Alex Teulé, David E. Goldgar, Ans M.W. van den Ouweland, Anna Jakubowska, Angela R. Bradbury, Dominique Stoppa-Lyonnet, Carole Brewer, Zsofia K. Stadler, Nadine Tung, Eric Hahnen, Vijai Joseph, Grzegorz Sukiennicki, Siranoush Manoukian, Debra Frost, Maria A. Caligo, Andrew K. Godwin, Christian Sutter, Bernard Peissel, Andrea L. Richardson, Kim De Leeneer, Antonis C. Antoniou, Florentia Fostira, Lesley McGuffog, Matti A. Rookus, Mary Beth Terry, Saundra S. Buys, Fabienne Lesueur, Gustavo C. Rodriguez, Julian Adlard, Barbara Wappenschmidt, Marinus J. Blok, Yael Laitman, Rob B. van der Luijt, Thomas Hansen, Francesca Damiola, Katherine L. Nathanson, Silje Nord, Kai Ren Ong, Ana Osorio, Katie Snape, Fergus J. Couch, John L. Hays, Walter Just, Ute Hamann, Silvia Tognazzo, Payal D. Shah, Valérie Bonadona, Ida Marie Heeholm Sonderstrup, Lídia Feliubadaló, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Research Council, Cancer Research UK (Reino Unido), Post-cancer GWAS Initiative, United States Department of Defense, Research Council of Lithuania, Asociación Española Contra el Cáncer, Red Temática de Investigación Cooperativa en Cáncer (España), Fondation ARC pour la recherche sur le cancer, Canadian Institutes of Health Research, Ministère de Économie, Innovation et Exportation (Canadá), University of Kansas. Cancer Center (Estados Unidos), Deutsche Krebshilfe, Leipzig Research Centre for Civilization Diseases, Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI), Instituto de Salud Carlos III, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Transcan Grant JTC Cancer, Hungarian Research Grants, Government of Catalonia (España), Ministry of Health and Welfare (Corea del Sur), United States of Department of Health & Human Services, State Budget of the Czech Republic (RECAMO), Charles University (República Checa), Westat (Estados Unidos), Russian Foundation for Basic Research, GOG Foundation. Gynecologic Oncology Group, Italian Association for Cancer Research, Clinical Genetics, CCA - Cancer biology and immunology, Human genetics, Epidemiology and Data Science, Human Genetics, Leslie, Goska [0000-0001-5756-6222], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medicum, Clinicum, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
Subjects: 0301 basic medicine, Genetic modifiers, Cancer Research, Epidemiology, Genes, BRCA2, BRCA1 and BRCA2 mutation carriers, Genes, BRCA1, Gene Expression, Gene mutation, DISEASE, Breast cancer, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, INVESTIGATORS, mutation carriers, skin and connective tissue diseases, Genetics, 1184 Genetics, developmental biology, physiology, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Oncology, Female, Differential allelic expression, Risk, Heterozygote, 3122 Cancers, Quantitative Trait Loci, NPAT, Single-nucleotide polymorphism, Locus (genetics), Breast Neoplasms, Quantitative trait locus, Biology, OVARIAN-CANCER, 03 medical and health sciences, CYCLIN E-CDK2, SDG 3 - Good Health and Well-being, Journal Article, medicine, Genetic predisposition, Genetic susceptibility, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Allele, BRCA1 and BRCA2, Alleles, Genetic association, HUMAN-CELLS, Chromosomes, Human, Pair 11, CONSORTIUM, Genetic Variation, DNA, medicine.disease, 030104 developmental biology, Mutation, Cis-regulatory variants, 3111 Biomedicine
Abstract: PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk. Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under Grant Agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-cancer GWAS Initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112: the GAME-ON Initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. BCFR: this work was supported by Grant UM1 CA164920 from the National Cancer Institute. BFBOCC was supported by Lithuania (BFBOCC-LT): Research Council of Lithuania Grant SEN-18/2015. BIDMC was supported by the Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA) was supported by Grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CNIO: this work was partially supported by Spanish Association Against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA), and SAF2010-20493. COH-CCGCRN: patients were recruited for this study from the City of Hope Clinical Cancer Genomics Community Research Network, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONSIT Team: Associazione Italiana Ricerca sul Cancro (AIRC) to P. Peterlongo (IG 2012 Id. 12821) and P. Radice (IG 2014 Id. 15547). Funds from Italian citizens who allocated the 5 9 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional Strategic Projects '5x1000') to S. Manoukian. FiorGen Foundation for Pharmacogenomics to L. Papi. CORE: the CIMBA Data Management and Data Analysis were supported by Cancer Research: UK Grants C12292/A20861, C12292/A11174. ACA is a Cancer Research-UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. J. Lecarpentier has been financially supported by the Fondation ARC (FONDATION ARC, 9 rue Guy Moquet 94803 Villejuif: France), Grant Number SAE20131200623. This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie, Innovation et Exportation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. This work was also supported by the Ministere de l'Economie, Innovation et Exportation du Quebec: Grant No. PSR-SIIRI-701. DEMOKRITOS: this research has been co-financed by the European Union (European Social Fund: ESF) and Greek National Funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF): Research Funding Program of the General Secretariat for Research and Technology: SYN11_10_19 NBCA. Investing in Knowledge Society through the European Social Fund. The DKFZ Study was supported by the DKFZ. EMBRACE was supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo were supported by an NIHR Grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust were supported by an NIHR Grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft were supported by Cancer Research UK Grant C5047/A8385. Ros Eeles was also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: the authors acknowledge the support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) was supported by the German Cancer Aid (Grant No. 110837, Rita K. Schmutzler). This work was supported by the European Regional Development Fund and Free State of Saxony, Germany (LIFE: Leipzig Research Centre for Civilization Diseases, Project Numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: the study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program and the French National Institute of Cancer (INCa). GEORGETOWN: CI received support from the Non-therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI Grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical GenomicsResearch, and Swing Fore the Cure. G-FAST: Bruce Poppe is a Senior Clinical Investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC was supported by a Grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER Funds. The HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON Study was supported by the Dutch Cancer Society Grants NKI1998-1854, NKI2004-3088, and NKI2007-3756, the Netherlands Organization of Scientific Research Grant NWO 91109024, the Pink Ribbon Grants 110005 and 2014-187.WO76, the BBMRI Grant NWO 184.021.007/CP46, and the Transcan Grant JTC 2012 Cancer 12-054. HEBON thanks the Registration Teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for their help in part of the data collection. HRBCP was supported by the Hong Kong Sanatorium and Hospital, Dr. Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health 1R 03CA130065, and North California Cancer Center. Hungarian Breast and Ovarian Cancer Study (HUNBOCS) was supported by Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: Contract Grant Sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract Grant Numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290, and 2014SGR364. The IHCC was supported by Grant PBZ_KBN_122/P05/2004. The ILUH Group was supported by the Icelandic Association "Walking for Breast Cancer Research" and by the Landspitali University Hospital Research Fund. INHERIT: this work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" Program: Grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade: Grant No. PSR-SIIRI-701. The PERSPECTIVE Project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (Grant GPH-129344), the Ministere de l'Economie, Science et Innovation du Quebec through Genome Quebec, and the Quebec Breast Cancer Foundation. IOVHBOCS was supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto Grant. IPOBCS: this study was in part supported by Liga Portuguesa Contra o Cancro. kConFab was supported by a Grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. KOHBRA was supported by a Grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (1020350). MAYO was supported by NIH Grants CA116167, CA192393, and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a Grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD was supported by MH CZ: DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague Project UNCE204024 (MZ). MSKCC was supported by Grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund. NAROD: 1R01 CA149429-01. NCI: the research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by Support Services Contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD. NICCC was supported by Clalit Health Services in Israel. Some of its activities were supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: this work has been supported by the Russian Federation for Basic Research (Grants 15-04-01744 and 16-54-00055). NRG Oncology: this study was supported by NRG Oncology Operations Grant Number U10 CA180868 as well as NRG SDMC Grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469), and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai, and Savage were supported by Funding from the Intramural Research Program, NCI. OSUCCG was supported by the Ohio State University Comprehensive Cancer Center. PBCS: this work was supported by the Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) Grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06), and Cancer Research Initiatives Foundation. The SMC Team was in part sponsored by a Grant from the Israeli Cancer Association to the Israeli Consortium of Hereditary Breast Cancer. SWE-BRCA Collaborators were supported by the Swedish Cancer Society. UCHICAGO was supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032, and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. OIO is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR was supported by a Project Grant from CRUK to Paul Pharoah. UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the Cure, Basser Research Center for BRCA. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr. Karlan was funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. Sí
Published: 2017
Full Text: View/download PDF

30. Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome

Author: T. J. Kranenburg-de Koning, Christiane Zweier, K Van Roozendaal, K. H. de Waal, Demis Tserpelis, Anita Rauch, Marinus J. Blok, C. V. M. Steinbusch, Eric Smeets, C. T. R. M. Schrander-Stumpel, R Hennekam, Amsterdam Neuroscience, Amsterdam Public Health, Human Genetics, Paediatrics, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, MUMC+: DA KG Lab Centraal Lab (9), and University of Zurich
Subjects: Proband, Adult, Male, 2716 Genetics (clinical), Pediatrics, medicine.medical_specialty, 10039 Institute of Medical Genetics, Genetic counseling, Mothers, 610 Medicine & health, Genetic Counseling, Pitt–Hopkins syndrome, Haploinsufficiency, Biology, Germline, Frameshift mutation, Neurodevelopmental disorder, Transcription Factor 4, 1311 Genetics, Intellectual Disability, Pitt-Hopkins syndrome, Intellectual disability, Genetics, medicine, Humans, Hyperventilation, Child, Frameshift Mutation, Genetics (clinical), TCF4, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Mosaicism, Facies, familial occurrence, medicine.disease, Phenotype, somatic mosaicism, Child, Preschool, 570 Life sciences, biology, Female, Transcription Factors
Abstract: Steinbusch CVM, van Roozendaal KEP, Tserpelis D, Smeets EEJ, Kranenburg-de Koning TJ, de Waal KH, Zweier C, Rauch A, Hennekam RCM, Blok MJ, Schrander-Stumpel CTRM. Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome. Clin Genet 2013: 83: 73-77. (C) John Wiley & Sons A/S. Published by Blackwell Publishing Ltd, 2012 Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, unusual face and breathing abnormalities and can be caused by haploinsufficiency of TCF4. The majority of cases are sporadic. Somatic mosaicism was reported infrequently. We report on a proband with typical manifestations of PTHS and his younger brother with a less striking phenotype. In both, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4. The same mutation was found at low levels in DNA extracted from the mother's blood, urine and saliva. This report of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling. We suggest careful studies in parents of other patients with PTHS to determine the frequency of germline and somatic mosaicism for TCF4 mutations.
Published: 2013
Full Text: View/download PDF

31. Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing

Author: Demis Tserpelis, Rita D. Brandão, Encarna B. Gomez Garcia, Marinus J. Blok, Kees E. P. van Roozendaal, Klinische Genetica, Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction
Subjects: Genetics, Cancer Research, RNA splicing, BRCA2 gene, In silico, Intron, RNA, Biology, Molecular biology, BRCA1 gene, Exon, Breast cancer, Oncology, Exonic splice enhancer motifs, Genetic variation, Allele, Gene
Abstract: A subset of the unclassified variants (UVs) identified during genetic screening of BRCA1/2 genes may affect splicing. We assessed at RNA level the effect of four BRCA1 and ten BRCA2 UVs with a putative splice effect, as predicted in silico. The variants selected for this study were beyond the positions -1, -2 or +1, +2 from the exon, and were not previously described (n = 8) or their effect on splicing was not assessed previously (n = 6). Lymphocytes from UV carriers and healthy controls were cultured and treated with puromycin to prevent nonsense-mediated mRNA decay. The relative contribution of each allele to the various transcripts was assessed using combinations of allele-specific and transcript-specific primers. BRCA2 c.425G > T, c.7976+3_7976+4del and c.8754+3G > C give rise to aberrant transcripts BRCA2 Delta 4, BRCA2 Delta 17 and retention of 46nt of intron 21, respectively, and were considered pathogenic. BRCA1 c.4987-3C > G gives rise to BRCA1 Delta 17 that is likely pathogenic; however, residual expression of the full-length transcript from the variant allele could not be excluded. BRCA1 c.692C > T, c.693G > A and BRCA2 c.6935A > T, besides expressing the full-length transcript, increased expression of BRCA1 Delta 11 and BRCA2 Delta 12, respectively. As these are naturally occurring isoforms, also observed in controls, the clinical relevance is unclear. The seven remaining UVs did not affect splicing and three intronic variants were therefore classified as neutral. In conclusion, the RNA analysis results clarified the clinical relevance of 6 of the 14 studied UVs and thereby greatly improve the genetic counselling of high-risk breast/ovarian cancer patients carrying these classified variants.
Published: 2011
Full Text: View/download PDF

32. MLL2 Mutation Spectrum in 45 Patients with Kabuki Syndrome

Author: Marinus J. Blok, Joep P.M. Geraedts, Thomy de Ravel, Demis Tserpelis, Aimee D C Paulussen, Raoul C.M. Hennekam, Eric Smeets, Constance T.R.M. Schrander-Stumpel, Maaike Vreeburg, Hubert J T Smeets, Irene Stolte-Dijkstra, Wilhelmina S. Kerstjens-Frederikse, Marie José H. Van Den Boogaard, J. J. P. Schrander, Grazia M.S. Mancini, Jean-Pierre Fryns, Annemieke M. A. Wagemans, Marja W. Wessels, Y. Detisch, Koenraad Devriendt, Arie van Haeringen, Alexander P.A. Stegmann, Crool Posma-Velter, Jasper J. van der Smagt, Amsterdam Neuroscience, Amsterdam Public Health, Paediatrics, Family Medicine, Kindergeneeskunde, RS: GROW - School for Oncology and Reproduction, Klinische Genetica, Clinical Genetics, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], School for Oncology & Developmental Biology (GROW), Department of Clinical Genetics, Department of Paediatrics, Department of Medical Genetics, University Medical Center [Utrecht], Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Department of Genetics, University Medical Center Groningen [Groningen] (UMCG), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Human Genetics, Erasmus University Rotterdam, Department of Pediatrics, Academic Medical Center, University of Amsterdam [Amsterdam] (UvA), Center for Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Clinical sciences, Medical Genetics, and Pediatrics
Subjects: Male, Hematologic Diseases/genetics, Biology, medicine.disease_cause, PROTEIN LYSINE METHYLTRANSFERASES, Frameshift mutation, Exon, Neoplasm Proteins/genetics, EARS, Abnormalities, Multiple/genetics, Genetics, medicine, Missense mutation, Humans, Abnormalities, Multiple, histone methyl transferase, Epigenetics, Gene, Genetics (clinical), Mutation, Kabuki syndrome, Life Sciences, MAKE-UP-SYNDROME, Face/abnormalities, medicine.disease, Molecular biology, Hematologic Diseases, GENE, Vestibular Diseases/genetics, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, KS, Histone methyltransferase, Face, MLL2, GROWTH, Female, DNA-Binding Proteins/genetics, MENTAL-RETARDATION
Abstract: Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS.© 2010 Wiley-Liss, Inc. PMID: 21280141 [PubMed - in process]
Published: 2011
Full Text: View/download PDF

33. Common Genetic Variation at BARD1 Is Not Associated with Breast Cancer Risk in BRCA1 or BRCA2 Mutation Carriers

Author: Maria A. Caligo, Carol Chu, Xianshu Wang, Senno Verhoef, Joanne L. Blum, Bruno Buecher, Amanda B. Spurdle, Theo A. M. van Os, Per Karlsson, Olga M. Sinilnikova, Sue Healey, Hanne Meijers-Heijboer, Georgia Chenevix-Trench, Marinus J. Blok, Timothy R. Rebbeck, Douglas F. Easton, Mary B. Daly, Annelie Liljegren, Margaret Cook, Christina G. Selkirk, Dominique Stoppa-Lyonnet, Mieke Kriege, Nadine Tung, Muriel Belotti, Susan Peock, Fiona Lalloo, Louise Izatt, Mads Thomassen, Henry T. Lynch, Christian F. Singer, Susan M. Domchek, Margreet G. E. M. Ausems, Tomasz Byrski, Olufunmilayo I. Olopade, Noralane M. Lindor, Claudine Isaacs, Katherine L. Nathanson, Gail E. Tomlinson, Clare Oliver, Hans Ehrencrona, Anna Jakubowska, Francine Durocher, Pascal Pujol, Debra Frost, Tuomas Heikkinen, Christine Lasset, Rosemarie Davidson, Jan Lubinski, Marie Agnés Collonge-Rame, Patricia A. Ganz, Nicoline Hoogerbrugge, Fergus J. Couch, Lesley McGuffog, Matti A. Rookus, Heli Nevanlinna, Helena Jernström, Sylvie Mazoyer, Jonathan Beesley, Judy Garber, Diana Eccles, Don M. Conroy, Xiaoqing Chen, Daphne Gschwantler-Kaulich, Tomasz Huzarski, Carole Verny-Pierre, Antonis C. Antoniou, D. Gareth Evans, Louise Marquart, Juul T. Wijnen, Ros Eeles, Peter Devilee, Laure Barjhoux, Fei Wan, Anne Catharine Dressler, Susan L. Neuhausen, Jeff Weitzel, Hélène Dreyfus, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, Human genetics, CCA - Oncogenesis, Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction
Subjects: Oncology, medicine.medical_specialty, Heterozygote, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], endocrine system diseases, Genotype, Epidemiology, Ubiquitin-Protein Ligases, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Breast cancer, Risk Factors, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Germ-Line Mutation, 030304 developmental biology, BRCA2 Protein, 0303 health sciences, Cancer prevention, Hereditary cancer and cancer-related syndromes [ONCOL 1], BRCA1 Protein, Tumor Suppressor Proteins, Haplotype, Cancer, medicine.disease, Prognosis, 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, Cancer research, Female, Breast disease, SNP array
Abstract: Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71–1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59–1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032–8. ©2011 AACR.
Published: 2011
Full Text: View/download PDF

34. Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection

Author: Rita D. Brandão, J. J. T. van Harssel, Aimee D C Paulussen, Marinus J. Blok, E. B. Gomez Garcia, Y. Detisch, Maurice P. Zeegers, C. E. P. van Roozendaal, RS: NUTRIM - R4 - Gene-environment interaction, Genetica & Celbiologie, Populatie Genetica, and Complexe Genetica
Subjects: Male, Proband, Oncology, Cancer Research, SCORING SYSTEM, Genes, BRCA1, Bioinformatics, FAMILY-HISTORY, Brca1 2 mutation, 0302 clinical medicine, Genetics(clinical), Unclassified variants, Family history, skin and connective tissue diseases, Genetics (clinical), BRCAPRO, AMERICAN-SOCIETY, RISK, 0303 health sciences, BRCA1 Protein, Genetic Carrier Screening, UNKNOWN CLINICAL-SIGNIFICANCE, Pedigree, 3. Good health, SUSCEPTIBILITY GENES, Mutation probability, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, Algorithms, medicine.medical_specialty, Breast Neoplasms, Genetic Counseling, Biology, DNA-SEQUENCE VARIANTS, Article, OVARIAN-CANCER, OPTIMAL SELECTION, 03 medical and health sciences, Breast cancer, Internal medicine, medicine, Genetics, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Genetic Testing, Probability model, Myriad II, Probability, 030304 developmental biology, Genetic Variation, Cancer, medicine.disease, BRCA1, BRCA2, Human genetics, Mutation
Abstract: Considerable differences exist amongst countries in the mutation probability methods and thresholds used to select patients for BRCA1/2 genetic screening. In order to assess the added value of mutation probability methods, we have retrospectively calculated the BRCAPRO and Myriad II probabilities in 306 probands who had previously been selected for DNA-analysis according to criteria based on familial history of cancer. DNA-analysis identified 52 mutations (16.9%) and 11 unclassified variants (UVs, 3.6%). Compared to cancer history, a threshold > or = 10% with BRCAPRO or with Myriad II excluded about 40% of the patients from analysis, including four with a mutation and probabilities 20% with BRCAPRO and Myriad II. In summary, BRCAPRO and Myriad II are more efficient than cancer history alone to exclude patients without a mutation. BRCAPRO performs better for the detection of BRCA1 mutations than of BRCA2 mutations. The Myriad II scores provided no additional information than the BRCAPRO scores alone for the detection of patients with a mutation. The use of thresholds excluded from analysis the majority of patients carrying an UV.
Published: 2010

35. The unfolding clinical spectrum of POLG mutations

Author: Esther Brusse, Bwee Tien Poll-The, C.E.M. de Die-Smulders, B.J.C. van den Bosch, E L C Jongen, Jörgen Bierau, Marinus J. Blok, Jessica E. Hoogendijk, I.F.M. de Coo, H.J.M. Smeets, Alexandra T.M. Hendrickx, M. de Visser, Neurology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Amsterdam Neuroscience, Paediatric Neurology, and Faculteit der Geneeskunde
Subjects: Adult, Male, medicine.medical_specialty, Ophthalmoplegia, Chronic Progressive External, Neuromuscular disease, Adolescent, DNA Mutational Analysis, Molecular Sequence Data, DNA-Directed DNA Polymerase, Biology, Primary Ovarian Insufficiency, medicine.disease_cause, DNA, Mitochondrial, Cohort Studies, Gene Frequency, Genetics, medicine, Humans, Clinical significance, Computer Simulation, Amino Acid Sequence, Child, Gene, Genetics (clinical), Aged, Mutation, Middle Aged, medicine.disease, Phenotype, Premature ovarian failure, DNA Polymerase gamma, Pedigree, Child, Preschool, Medical genetics, Female, Chronic progressive external ophthalmoplegia, Sequence Alignment
Abstract: Background: Mutations in the DNA polymerase-γ ( POLG ) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions. Objective: To determine the spectrum of POLG mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype–phenotype correlations. Results: The authors identified 64 predominantly recessive mutations in 37 patients from a total of 232 patients, consisting of 23 different mutations. The substitution p.A467T was most frequently observed (n = 23), but was as frequent in childhood cases as in adult cases. Five new pathogenic recessive mutations, p.Lys925ArgfsX42, p.R275X, p.G426S, p.A804T and p.R869Q were identified. The known dominant chronic progressive external ophthalmoplegia (CPEO) mutation p.R943H was for the first time associated with premature ovarian failure as well. In 19 patients the authors identified only a single recessive mutation, or a sequence variant with unclear clinical significance. The data substantiate earlier observations that in POLG patients a fatal status epilepticus and liver failure can be triggered by sodium valproate. It is therefore important to exclude POLG mutations before administering this treatment. Conclusion: The clinical features of the patient are the most important features to select putative POLG mutation carriers and not the presence of mtDNA deletions or OXPHOS (oxidative phosphorylation) activity. The authors conclude that POLG mutations are an important cause of heterogeneous mitochondrial pathology and that more accurate genotype–phenotype correlations allow a more rapid genetic diagnosis and improved prognosis for mutation carriers.
Published: 2009

36. Impact of Two Functional Progesterone Receptor Polymorphisms (PRP): +331G/A and PROGINS on the Cancer Risks in Familial Breast/Ovarian Cancer

Author: Dagmar-C. Fischer, Y. Detisch, Encarna B. Gomez-Garcia, H. Baars, Andrea Romano, Patrick J. Lindsey, Rita D. Brandão, R.x Martens, E. Jongen, Marinus J. Blok, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, RS: GROW - School for Oncology and Reproduction, Gynaecologie en Obstetrie, Genetica & Celbiologie, and Populatie Genetica
Subjects: Proband, Cancer Research, medicine.medical_specialty, Mutation, endocrine system diseases, Cancer, Biology, medicine.disease, medicine.disease_cause, Endocrinology, Oncology, Internal medicine, Progesterone receptor, medicine, Allele, skin and connective tissue diseases, Ovarian cancer, CHEK2, Gene
Abstract: Background: More than half of the families with breast and/or ovarian cancer (BC/OC) have no BRCA1 or BRCA2 mutation, moreover the broad lifetime risks reported within families with a BRCA1/2 mutation suggest other genes are also responsible. Objective: Assess the prevalence, gene-gene and phenotype-genotype associations of two functional progesterone receptor polymorphisms (PRP), PROGINS and +331G/A, in familial BC/OC. Methods: DNA samples from 318 randomly selected probands tested for BRCA1/2 mutations were genotyped for the PRP and CHEK2*1100delC variant. Results: BRCA1 was associated with BC at young age, p=0.002; +331A marginally with OC, p=0.07, and PROGINS with male BC, p=0.04. Homozygous +331A/A co-segregated with BRCA2 variants more frequently than expected by chance alone. Co-occurrence of +331A with a BRCA1BRCA2 mutation was associated with multiple BC events compared to +331A or BRCA1/BRCA2 alone, p=0.02. Conclusions: The PRP are risk factors for familial BC/OC, and +331A allele is a gene modifier of BRCA1 and BRCA2.
Published: 2007
Full Text: View/download PDF

37. No evidence to support an association ofPER3clock gene polymorphism with ADHD-related idiopathic chronic sleep onset insomnia

Author: Simon Archer, K. Spee, Marcel Smits, K.B. van der Heijden, L.M.G. Curfs, B. Gunning, Marinus J. Blok, Populatie Genetica, Klinische Genetica, Cognitive Neuroscience, RS: FPN CN II, and RS: GROW - School for Oncology and Reproduction
Subjects: medicine.medical_specialty, Pediatrics, Physiology, business.industry, Delayed sleep phase, Odds ratio, medicine.disease, Melatonin, CLOCK, PER3, Circadian rhythm sleep disorder, Endocrinology, Physiology (medical), Internal medicine, mental disorders, medicine, Insomnia, medicine.symptom, Sleep onset, business, Ecology, Evolution, Behavior and Systematics, medicine.drug
Abstract: Idiopathic chronic sleep onset insomnia (SOI) in children with Attention-Deficit/Hyperactivity Disorder (ADHD) shows typical characteristics of the delayed sleep phase syndrome and could, therefore, be considered a circadian rhythm sleep disorder. A variable number tandem repeat (VNTR) polymorphism of the clock gene PER3 is associated with the delayed sleep phase syndrome and, hence, may associate with ADHD-related chronic SOI as well. Here, we investigated an association between ADHD-related chronic SOI and the VNTR polymorphism of PER3 in 10 medication naive children with rigorously diagnosed ADHD and SOI (ADHD-SOI), and in 10 normal controls. Actigraphic sleep onset and sleep duration and salivary dim light melatonin onset (DLMO) were evaluated in ADHD-SOI. The 4-repeat allele frequency was lower in ADHD-SOI (0.65) than in normal controls (0.75) ( p =0.73) with an odds ratio of 0.62 (CI 0.16-2.4). In ADHD-SOI, mean (SD) DLMO (21:380:50 h), sleep onset (22:170:46 h), and sleep duration (9:260:41 h) were not significantly related to the 4-repeat allele frequency. The present findings suggest no association between ADHD-related idiopathic chronic sleep onset insomnia and the PER3 VNTR polymorphism.
Published: 2005
Full Text: View/download PDF

38. Identification and characterization of two antisense transcripts from the major immediate early region of rat cytomegalovirus

Author: Gert Grauls, Marinus J. Blok, Cornelis Vink, Cathrien A. Bruggeman, K. W. R. van Cleef, and Kim G.M. Savelkouls
Subjects: Muromegalovirus, Molecular Sequence Data, Biology, medicine.disease_cause, Salivary Glands, Virus, Herpesviridae, Immediate-Early Proteins, RNA, Complementary, Transcription (biology), Betaherpesvirinae, Virology, Sense (molecular biology), Leukocytes, Pi, medicine, Animals, RNA, Antisense, Amino Acid Sequence, RNA, Messenger, Antigens, Viral, Messenger RNA, Base Sequence, Embryo, General Medicine, Fibroblasts, biology.organism_classification, Molecular biology, Rats, RNA, Viral
Abstract: We have identified and characterized two antisense transcripts from the rat cytomegalovirus (RCMV) major immediate early (MIE) region. These transcripts, designated IE-AS1 and IE-AS2, are complementary to part of the sense IE1 transcript. The IE-AS transcripts were first detected in peripheral blood leukocytes (PBL) of RCMV-infected rats at 7 days post-infection (pi) in the absence of IE1 transcription. Nevertheless, both the IE1 and IE-AS transcripts were found at the same time in the salivary glands of RCMV-infected rats at 7 and 120 days pi as well as in RCMV-infected rat embryo fibroblasts (REFs) at 48 h pi.
Published: 2005
Full Text: View/download PDF

39. Onset and duration of cytomegalovirus immediate early 1 mRNA expression in the blood of renal transplant recipients

Author: Angéla Lukácsi, Valère J. Goossens, Johannes P. van Hooff, Peter Terporten, Cathrien A. Bruggeman, Maarten H. L. Christiaans, Marinus J. Blok, and Peter Sillekens
Subjects: Adult, Male, Human cytomegalovirus, Time Factors, Prednisolone, viruses, Urinary system, Cytomegalovirus, medicine.disease_cause, Herpesviridae, Virus, Immediate-Early Proteins, Viral Matrix Proteins, Viral Proteins, Viral Envelope Proteins, Betaherpesvirinae, Virology, medicine, Humans, RNA, Messenger, Glucocorticoids, Self-Sustained Sequence Replication, Aged, Kidney, biology, Age Factors, virus diseases, Middle Aged, Phosphoproteins, biology.organism_classification, medicine.disease, Kidney Transplantation, Transplantation, Infectious Diseases, medicine.anatomical_structure, Cytomegalovirus Infections, Immunology, RNA, Viral, Female, medicine.drug
Abstract: Human cytomegalovirus (CMV) messenger (m) RNA expression in circulating leukocytes reflects directly viral activity in the human host. In this study, sixty-nine patients were monitored prospectively for CMV infection and mRNA expression during the first year after renal transplantation. Of the 69 recipients, 58 (84%) recipients were positive for CMV immediate early 1 (IE1) mRNA as detected by nucleic acid sequence-based amplification. The median onset of IE1 expression started at day 22 after transplantation and continued for a median duration of 82 days. IE1 mRNA expression started significantly earlier in recipients who developed an active CMV infection (P = 0.001) and in mycophenolate mofetil (MMF) treated recipients (P = 0.002). The duration of IE1 mRNA expression was significantly longer in recipients that had previously an early onset of IE1 mRNA expression (P = 0.001) and in recipients with active CMV infection (P = 0.007). Remarkably, longer prednisolone intake was correlated with a significantly (P = 0.02) shorter duration of IE1 expression compared to a longer duration of IE1 expression in recipients with only a short prednisolone intake. In recipients infected with glycoprotein B (gB) type 1 CMV strains, the duration of IE1 expression was significantly (P = 0.04) shorter compared to recipients infected with non-gB type 1 CMV strains (64 days vs. 150 days). The study indicates that multiple factors play a role in the onset and/or duration of CMV IE1 mRNA expression, for example, MMF treatment, prednisolone intake, and gB type of the specific CMV strain. The clinical significance of these correlations remains to be studied in more detail. J. Med. Virol. 72:94–101, 2004. © 2004 Wiley-Liss, Inc.
Published: 2003
Full Text: View/download PDF

40. Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients

Author: Encarna B. Gomez-Garcia, Rick Kamps, Sofia Xanthoulea, Balazs Jori, E. J. Speel, B. Delvoux, Marinus J. Blok, Felicia Trups Oei, Carli M. J. Tops, Roy F.P.M. Kruitwagen, Koen Van de Vijver, Bart de Koning, Andrea Romano, Obstetrie & Gynaecologie, Ondersteunend personeel CD, MUMC+: DA KG Lab Centraal Lab (9), Pathologie, MUMC+: MA Medische Staf Obstetrie Gynaecologie (9), MUMC+: DA KG Polikliniek (9), Klinische Genetica, RS: GROW - Developmental Biology, RS: GROW - Oncology, RS: GROW - R2 - Basic and Translational Cancer Biology, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: Oncology, Kaplan-Meier Estimate, SUSCEPTIBILITY, COLORECTAL-CANCER, Gene Frequency, Risk Factors, Medicine and Health Sciences, MUTATION, Genetics, Aged, 80 and over, next generation sequencing, RISK, Molecular pathology, High-Throughput Nucleotide Sequencing, genetic risk modifier, Middle Aged, Prognosis, Immunohistochemistry, Lynch syndrome, Phenotype, endometrial cancer, Medical genetics, Female, EPIDERMAL-GROWTH-FACTOR, Research Paper, estrogens, Adult, medicine.medical_specialty, Genotype, Genetic counseling, TUMOR TYPES, Polymorphism, Single Nucleotide, Germline mutation, Internal medicine, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele frequency, Germ-Line Mutation, Aged, Proportional Hazards Models, business.industry, Endometrial cancer, Cancer, ENDOMETRIAL CANCER, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Endometrial Neoplasms, DISCOVERY, business
Abstract: // Balazs Jori 1, 2 , Rick Kamps 4, * , Sofia Xanthoulea 1, * , Bert Delvoux 1 , Marinus J. Blok 2 , Koen K. Van de Vijver 3, 6 , Bart de Koning 2 , Felicia Trups Oei 2 , Carli M. Tops 5 , Ernst J. M. Speel 3 , Roy F. Kruitwagen 1 , Encarna B. Gomez-Garcia 2 , Andrea Romano 1 1 Department of Gynecology and Obstetrics, GROW – School for Oncology & Developmental Biology, Maastricht University Medical Centre, The Netherlands 2 Department of Clinical Genetics, GROW – School for Oncology & Developmental Biology, Maastricht University Medical Centre, The Netherlands 3 Department of Pathology, GROW – School for Oncology & Developmental Biology, Maastricht University Medical Centre, The Netherlands 4 Department of Clinical Genetics, Genomics & Bioinformatics, CARIM – School for Cardiovascular Diseases, Maastricht University Medical Centre, The Netherlands 5 Department of Clinical Genetics, Leiden University Medical Centre, The Netherlands 6 Current address: Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands * These authors have contributed equally to this work Correspondence to: Andrea Romano, e-mail: a.romano@maastrichtuniversity.nl Keywords: Lynch syndrome, endometrial cancer, genetic risk modifier, next generation sequencing, estrogens Received: June 18, 2015 Accepted: October 09, 2015 Published: October 22, 2015 ABSTRACT Background: The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. Methods: A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. Results: A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. Conclusion: A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.
Published: 2015

41. A rat cytomegalovirus strain with a disruption of the r144 MHC class I-like gene is attenuated in the acute phase of infection in neonatal rats

Author: Marinus J. Blok, Jeroen S. Kloover, Gert Grauls, Cathrien A. Bruggeman, and Cornelis Vink
Subjects: Male, Muromegalovirus, Time Factors, Genes, MHC Class I, Cell Count, Spleen, Major histocompatibility complex, medicine.disease_cause, Salivary Glands, Herpesviridae, Virus, Natural killer cell, Viral Proteins, Virology, MHC class I, Leukocytes, medicine, Animals, biology, Macrophages, Wild type, Herpesviridae Infections, General Medicine, Rats, Disease Models, Animal, Titer, medicine.anatomical_structure, Animals, Newborn, Acute Disease, DNA, Viral, biology.protein, Female, Gene Deletion
Abstract: We previously generated an RCMV strain in which the r144 gene, encoding a major histocompatibility complex class I homolog, had been deleted (RCMVdelta r144). To investigate the role of r144 during acute infection of neonatal rats, we infected three days-old neonatal rats with either RCMVdelta r144 or wild type (wt) RCMV and the presence of infectious virus as well as viral DNA in various organs was determined at either 3, 5 or 21 days p.i.. In addition, we assessed both type and number of inflammatory cells in these organs. Interestingly, a significantly lower concentration of infectious virus as well as viral DNA was found in spleens of RCMVdelta r144-infected rats than in those of wt RCMV-infected animals at 3 days p.i.. At the same time point, a significantly lower amount of infiltrating NK cells and monocytes/macrophages was seen in the spleens of RCMVdelta r144-infected rats than in spleens of rats infected with wt RCMV. At 21 days p.i., RCMVdelta r144-infected rats were found to have lower virus titers in the salivary glands than wt RCMV-infected animals. Significant differences between RCMVdelta r144- and wt RCMV-infected rats were detected neither at other time points nor at other sites. We conclude that after infection of neonatal rats, the replication of RCMVdelta r144 is severely restricted compared to wt RCMV.
Published: 2002
Full Text: View/download PDF

42. CYTOMEGALOVIRUS INFECTION, VIRAL DNA, AND IMMEDIATE EARLY-1 GENE EXPRESSION IN REJECTING RAT LIVER ALLOGRAFTS1

Author: Timi Martelius, Krister Höckerstedt, Irmeli Lautenschlager, Cathrien A. Bruggeman, Marinus J. Blok, Kaija Inkinen, and Raisa Loginov
Subjects: Human cytomegalovirus, 0303 health sciences, Transplantation, Bile duct, medicine.medical_treatment, Congenital cytomegalovirus infection, Immunosuppression, In situ hybridization, Biology, medicine.disease, biology.organism_classification, medicine.disease_cause, Virology, Herpesviridae, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Betaherpesvirinae, Immunology, medicine, 030211 gastroenterology & hepatology, 030304 developmental biology
Abstract: Background. Cytomegalovirus (CMV) infection has been linked to acute and chronic rejection. We have previously shown that concomitant rat cytomegalovirus (RCMV) infection increases portal inflammation and bile duct destruction in rejecting rat liver allografts. Many of the pro-inflammatory effects of CMV have been attributed to the immediate early (IE) proteins of CMV. We wanted to investigate whether RCMV and IE-1 gene expression persist in the liver graft in our model. Methods. Liver transplantations were performed from PVG (RT1c) into BN (RT1n) rats. One day after transplantation, the rats were infected with RCMV. No immunosuppression was given. The graft infection was studied by viral culture, immunofluorescence, DNA in situ hybridization and RT-PCR for the detection of IE-1 mRNA at various time points. Results. RCMV caused an active infection from 5 days to 2 weeks after transplantation, during which infectious virus was found in the graft. Thereafter the cultures were negative. RCMV antigens and DNA were found in hepatocytes, endothelial, inflammatory, and bile duct cells during the active infection. At 4 weeks, RCMV DNA positive hepatocytes, endothelial, inflammatory, and bile duct cells could still be found, but in much smaller quantities. IE-1 mRNA expression was, however, only detected during the active infection, not at 4 weeks postinfection. Conclusions. RCMV IE-1 expression does not persist in the graft after the active infection, although some viral DNA can be detected in the graft up to 4 weeks. In our model, the CMV-induced increase in graft damage does not seem to require the continued expression of IE-1.
Published: 2001
Full Text: View/download PDF

43. Diagnostic Implications of Human Cytomegalovirus Immediate Early-1 and pp67 mRNA Detection in Whole-Blood Samples from Liver Transplant Patients Using Nucleic Acid Sequence-Based Amplification

Author: Valère J. Goossens, Irmeli Lautenschlager, Krister Höckerstedt, Cornelis Vink, Jaap M. Middeldorp, Marinus J. Blok, and Cathrien A. Bruggeman
Subjects: Adult, Microbiology (medical), Ganciclovir, Human cytomegalovirus, Congenital cytomegalovirus infection, Cytomegalovirus, Biology, medicine.disease_cause, Herpesviridae, Immediate early protein, Immediate-Early Proteins, Viral Proteins, 03 medical and health sciences, Betaherpesvirinae, Virology, parasitic diseases, medicine, Humans, RNA, Messenger, Viremia, Antigens, Viral, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Gene Amplification, virus diseases, Phosphoproteins, medicine.disease, biology.organism_classification, NASBA, Liver Transplantation, Transplantation, medicine.drug
Abstract: Nucleic acid sequence-based amplification (NASBA) was used for detection of the human cytomegalovirus (CMV) immediate early-1 (IE) and the late pp67 mRNA in 353 blood samples collected from 34 liver transplant patients. The diagnostic value of these assays was compared to that of the pp65 antigenemia assay. Overall, 95 and 42% of the antigenemia-positive samples were IE NASBA and pp67 NASBA positive, respectively. Although the results from pp67 NASBA and the antigenemia assay appeared to correspond poorly, a clear correlation was seen between pp67 NASBA-negative results and low numbers of pp65 antigen-positive cells. Twenty patients (59%) were treated with ganciclovir after the diagnosis of symptomatic CMV infection. Before initiation of the antiviral therapy, the antigenemia assay detected the onset of symptomatic infection in all patients, whereas 95 and 60% of these patients were IE NASBA and pp67 NASBA positive, respectively. Although the sensitivity of IE NASBA was very high, the positive predictive value (PPV) of this assay for the onset of a symptomatic infection was only 63%. The PPV of the antigenemia assay as well as pp67 NASBA was considerably higher (80 and 86%, respectively). Thus, the detection of IE mRNA using NASBA appears to be particularly useful as a marker for early initiation of antiviral therapy in patients at high risk for the development of a symptomatic infection. Also, IE NASBA was found to be more sensitive than the antigenemia assay for monitoring CMV infection during antiviral therapy. On the contrary, pp67 NASBA did not appear to have additional diagnostic value compared to the antigenemia assay.
Published: 2000
Full Text: View/download PDF

44. EARLY DETECTION OF HUMAN CYTOMEGALOVIRUS INFECTION AFTER KIDNEY TRANSPLANTATION BY NUCLEIC ACID SEQUENCE-BASED AMPLIFICATION1

Author: Valère J. Goossens, Marinus J. Blok, M. H. L. Christiaans, Cathrien A. Bruggeman, J.P. van Hooff, Peter Sillekens, and Jaap M. Middeldorp
Subjects: Human cytomegalovirus, Transplantation, Congenital cytomegalovirus infection, Biology, medicine.disease_cause, medicine.disease, biology.organism_classification, Virology, NASBA, Herpesviridae, Immediate early protein, Serology, Betaherpesvirinae, parasitic diseases, Immunology, medicine
Abstract: Background. The early detection of human cytomegalovirus infection after organ transplantation is a prerequisite for effective antiviral therapy. We evaluated the diagnostic value of monitoring the viral immediate-early (IE) 1 mRNA expression in blood leukocytes by nucleic acid sequence-based amplification (NASBA). Methods. Nucleic acids were isolated from 489 blood samples collected from 42 kidney transplant recipients and subjected to amplification by IE NASBA The IE NASBA results were compared to those from pp67 NASBA, pp65 antigenemia, cell culture (DEAFF and CPE), and serology. Results. IE NASBA provedl to be the most sensitive assay which detected the onset of both primary and secondary cytomegalovirus infection significantly earlier than the other assays. Conclusions. The early detection of cytomegalovirus infection with IE NASBA would enable the start of effective antiviral therapy at an early state of infection to prevent cytomegalovirus disease in patients at risk.
Published: 1999
Full Text: View/download PDF

45. Diagnostic value of nucleic-acid-sequence- based amplification for the detection of cytomegalovirus infection in renal and liver transplant recipients

Author: J.P. van Hooff, Valère J. Goossens, Krister Höckerstedt, Peter Sillekens, Marinus J. Blok, Irmeli Lautenschlager, Jaap M. Middeldorp, Cathrien A. Bruggeman, M. H. L. Christiaans, Pathology, CCA - Cancer immunology, CCA - Target Discovery & Preclinial Therapy Development, CCA - Biomarkers, CCA - Evaluation of Cancer Care, AII - Infectious diseases, and AII - Cancer immunology
Subjects: Virus Cultivation, Genes, Viral, medicine.medical_treatment, viruses, Congenital cytomegalovirus infection, Cytomegalovirus, Liver transplantation, Polymerase Chain Reaction, Immediate early protein, Serology, Immediate-Early Proteins, Viral Matrix Proteins, Postoperative Complications, Virology, parasitic diseases, medicine, Humans, RNA, Messenger, Antigens, Viral, Genes, Immediate-Early, Kidney transplantation, business.industry, Viral culture, virus diseases, Nucleic acid amplification technique, medicine.disease, Phosphoproteins, NASBA, Kidney Transplantation, Liver Transplantation, Infectious Diseases, surgical procedures, operative, Immunology, Cytomegalovirus Infections, RNA, Viral, business, Nucleic Acid Amplification Techniques
Abstract: To evaluate the diagnostic value of nucleic-acid-sequence-based amplification (NASBA) for the detection of cytomegalovirus (CMV) infection in transplant recipients, we compared immediate early 1 (IE1) and late pp67 mRNA detection by NASBA with the antigenemia assay, PCR and viral culture in 72 renal transplant (RTx) recipients and with antigenemia and serology in 25 liver transplant (LTx) recipients. Antigenemia, viral culture and pp67 NASBA were almost equivalent for the detection of CMV in RTx recipients. In LTx recipients, antigenemia detected more positive samples and more positive recipients compared to pp67 NASBA. In RTx recipients, PCR detected more positive samples and positive recipients compared to pp67 NASBA, antigenemia and viral culture. Also the first day of detection was slightly earlier for PCR. However, IE1 NASBA was the most sensitive test and detected 96% of all positive samples and positive transplant recipients. In addition, IE1 NASBA preceded PCR and all other positive results. This makes IE1 NASBA a very attractive screening test for the early detection of CMV infection.
Published: 1999
Full Text: View/download PDF

46. Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium

Author: Logan C. Walker, Paolo Radice, Ana Vega, Amanda B. Spurdle, Claudia Foglia, Mara Colombo, Marinus J. Blok, Giovanna De Vecchi, Barbara Wappenschmidt, Demis Tserpelis, Eduardo Díaz-Rubio, Alexandra Becker, Rita D. Brandão, Lindsay D. Smith, Mireia Menéndez, Ana Blanco, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Pilar Garre, Atocha Romero, Diana Baralle, James D. Fackenthal, Marta Santamariña, Trinidad Caldés, Phillip J. Whiley, Claude Houdayer, Sandra Bonache, Melissa A. Brown, Orland Diez, RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)
Subjects: Genetics, Messenger RNA, BRCA1 Protein, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Alternative splicing, Intron, Exonic splicing enhancer, Locus (genetics), General Medicine, Biology, Exon, Alternative Splicing, RNA splicing, Humans, Protein Isoforms, Female, Breast, RNA, Messenger, skin and connective tissue diseases, Molecular Biology, Genetics (clinical), Minigene
Abstract: Loss-of-function germline mutations in BRCA1 (MIM #113705) confer markedly increased risk of breast and ovarian cancer. The full-length transcript codifies for a protein involved in DNA repair pathways and cell-cycle checkpoints. Several BRCA1 splicing isoforms have been described in public domain databases, but the physiological role (if any) of BRCA1 alternative splicing remains to be established. An accurate description of 'naturally occurring' alternative splicing at this locus is a prerequisite to understand its biological significance. However, a systematic analysis of alternative splicing at the BRCA1 locus is yet to be conducted. Here, the Evidence-Based Network for the Interpretation of Germ-Line Mutant Alleles consortium combines RT-PCR, exon scanning, cloning, sequencing and relative semi-quantification to describe naturally occurring BRCA1 alternative splicing with unprecedented resolution. The study has been conducted in blood-related RNA sources, commonly used for clinical splicing assays, as well as in one healthy breast tissue. We have characterized a total of 63 BRCA1 alternative splicing events, including 35 novel findings. A minimum of 10 splicing events (Delta 1Aq, Delta 5, Delta 5q, Delta 8p, Delta 9, Delta(9,10), Delta 9_11, Delta 11q, Delta 13p and Delta 14p) represent a substantial fraction of the full-length expression level (ranging from 5 to 100%). Remarkably, our data indicate that BRCA1 alternative splicing is similar in blood and breast, a finding supporting the clinical relevance of blood-based in vitro splicing assays. Overall, our data suggest an alternative splicing model in which most non-mutually exclusive alternative splicing events are randomly combined into individual mRNA molecules to produce hundreds of different BRCA1 isoforms.
Published: 2014

47. A randomised controlled phase II trial of pre-operative celecoxib treatment reveals anti-tumour transcriptional response in primary breast cancer

Author: Marinus J. Blok, Bart de Vries, Jürgen Veeck, Hubert J.M. Smeets, P. Hupperets, Rita D. Brandão, Kristien Keymeulen, Koen Van de Vijver, Catharina H. M. J. Van Elssen, Vivianne C. G. Tjan-Heijnen, Torik A.Y. Ayoubi, Patrick J. Lindsey, RS: NUTRIM - R4 - Gene-environment interaction, RS: NUTRIM - R2 - Gut-liver homeostasis, Genetica & Celbiologie, Pathologie, Surgery, and Interne Geneeskunde
Subjects: Pathology, Colorectal cancer, COLORECTAL-CANCER, DOUBLE-BLIND, 0302 clinical medicine, Surgical oncology, Medicine and Health Sciences, POSTMENOPAUSAL PATIENTS, skin and connective tissue diseases, Oligonucleotide Array Sequence Analysis, GENE-EXPRESSION, Medicine(all), Sulfonamides, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Ductal, Breast, COLON-CANCER, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, Middle Aged, Cell cycle, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Female, MESSENGER-RNA, Research Article, medicine.drug, medicine.medical_specialty, Breast Neoplasms, Biology, Real-Time Polymerase Chain Reaction, ASPIRIN USE, 03 medical and health sciences, Breast cancer, Double-Blind Method, Biomarkers, Tumor, Carcinoma, medicine, Humans, Cyclooxygenase Inhibitors, RNA, Messenger, COMBINATION, 030304 developmental biology, PROSTAGLANDIN SYNTHASE, Gene Expression Profiling, medicine.disease, Gene expression profiling, Carcinoma, Lobular, Celecoxib, Cancer research, Pyrazoles, Neoplasm Grading, Follow-Up Studies
Abstract: INTRODUCTION: Cyclooxygenase-2 (COX-2) is frequently over-expressed in primary breast cancer. In transgenic breast cancer models, over-expression of COX-2 leads to tumour formation while COX-2 inhibition exerts anti-tumour effects in breast cancer cell lines. To further determine the effect of COX-2 inhibition in primary breast cancer, we aimed to identify transcriptional changes in breast cancer tissues of patients treated with the selective COX-2 inhibitor celecoxib. METHODS: In a single-centre double-blind phase II study, thirty-seven breast cancer patients were randomised to receive either pre-operative celecoxib (400 mg) twice daily for two to three weeks (n = 22) or a placebo according to the same schedule (n = 15). Gene expression in fresh-frozen pre-surgical biopsies (before treatment) and surgical excision specimens (after treatment) was profiled by using Affymetrix arrays. Differentially expressed genes and altered pathways were bioinformatically identified. Expression of selected genes was validated by quantitative PCR (qPCR). Immunohistochemical protein expression analyses of the proliferation marker Ki-67, the apoptosis marker cleaved caspase-3 and the neo-angiogenesis marker CD34 served to evaluate biological response. RESULTS: We identified 972 and 586 significantly up- and down-regulated genes, respectively, in celecoxib-treated specimens. Significant expression changes in six out of eight genes could be validated by qPCR. Pathway analyses revealed over-representation of deregulated genes in the networks of proliferation, cell cycle, extracellular matrix biology, and inflammatory immune response. The Ki-67 mean change relative to baseline was -29.1% (P = 0.019) and -8.2% (P = 0.384) in the treatment and control arm, respectively. Between treatment groups, the change in Ki-67 was statistically significant (P = 0.029). Cleaved caspase-3 and CD34 expression were not significantly different between the celecoxib-treated and placebo-treated groups. CONCLUSIONS: Short-term COX-2 inhibition by celecoxib induces transcriptional programs supporting anti-tumour activity in primary breast cancer tissue. The impact on proliferation-associated genes is reflected by a reduction of Ki-67 positive cells. Therefore, COX-2 inhibition should be considered as a treatment strategy for further clinical testing in primary breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01695226.
Published: 2013
Full Text: View/download PDF

48. Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification

Author: Rick Kamps, Andrea Romano, Bianca J.C. van den Bosch, Marinus J. Blok, Rita D. Brandão, Aimee D C Paulussen, and Sofia Xanthoulea
Subjects: 0301 basic medicine, Oncology, theranostics, Review, NEEDLE-ASPIRATION-CYTOLOGY, lcsh:Chemistry, 0302 clinical medicine, METASTATIC BREAST-CANCER, Neoplasms, gene-panel, BRCA2 MUTATION CARRIERS, diagnostics, Medicine, Exome, RESIDUAL DISEASE DETECTION, lcsh:QH301-705.5, Spectroscopy, inherited cancer syndrome, Clinical Trials as Topic, whole-exome-sequencing, High-Throughput Nucleotide Sequencing, Genomics, General Medicine, Prognosis, CLINICALLY ACTIONABLE MUTATIONS, Computer Science Applications, cancer somatic mutation, 030220 oncology & carcinogenesis, Cancer classification, medicine.medical_specialty, INHERITED COLORECTAL-CANCER, ACUTE MYELOID-LEUKEMIA, whole-genome-sequencing, Catalysis, DNA sequencing, Inorganic Chemistry, 03 medical and health sciences, Germline mutation, Neoplastic Syndromes, Hereditary, Internal medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, DIHYDROPYRIMIDINE DEHYDROGENASE GENE, Genetic Testing, Physical and Theoretical Chemistry, Liquid biopsy, Molecular Biology, business.industry, Organic Chemistry, Computational Biology, Reproducibility of Results, Data interpretation, Cancer, WHOLE-GENOME AMPLIFICATION, genetic modifiers, medicine.disease, CIRCULATING TUMOR-CELLS, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Pharmacogenetics, Mutation, next-generation sequencing, business, Genetic diagnosis
Abstract: Next-generation sequencing (NGS) technology has expanded in the last decades with significant improvements in the reliability, sequencing chemistry, pipeline analyses, data interpretation and costs. Such advances make the use of NGS feasible in clinical practice today. This review describes the recent technological developments in NGS applied to the field of oncology. A number of clinical applications are reviewed, i.e., mutation detection in inherited cancer syndromes based on DNA-sequencing, detection of spliceogenic variants based on RNA-sequencing, DNA-sequencing to identify risk modifiers and application for pre-implantation genetic diagnosis, cancer somatic mutation analysis, pharmacogenetics and liquid biopsy. Conclusive remarks, clinical limitations, implications and ethical considerations that relate to the different applications are provided.
Published: 2017
Full Text: View/download PDF

49. Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Author: Fergus J, Couch, Xianshu, Wang, Lesley, McGuffog, Andrew, Lee, Curtis, Olswold, Karoline B, Kuchenbaecker, Penny, Soucy, Zachary, Fredericksen, Daniel, Barrowdale, Joe, Dennis, Mia M, Gaudet, Ed, Dicks, Matthew, Kosel, Sue, Healey, Olga M, Sinilnikova, Adam, Lee, François, Bacot, Daniel, Vincent, Frans B L, Hogervorst, Susan, Peock, Dominique, Stoppa-Lyonnet, Anna, Jakubowska, Paolo, Radice, Rita Katharina, Schmutzler, Susan M, Domchek, Marion, Piedmonte, Christian F, Singer, Eitan, Friedman, Mads, Thomassen, Thomas V O, Hansen, Susan L, Neuhausen, Csilla I, Szabo, Ignacio, Blanco, Mark H, Greene, Beth Y, Karlan, Judy, Garber, Catherine M, Phelan, Jeffrey N, Weitzel, Marco, Montagna, Edith, Olah, Irene L, Andrulis, Andrew K, Godwin, Drakoulis, Yannoukakos, David E, Goldgar, Trinidad, Caldes, Heli, Nevanlinna, Ana, Osorio, Mary Beth, Terry, Mary B, Daly, Elizabeth J, van Rensburg, Ute, Hamann, Susan J, Ramus, Amanda Ewart, Toland, Maria A, Caligo, Olufunmilayo I, Olopade, Nadine, Tung, Kathleen, Claes, Mary S, Beattie, Melissa C, Southey, Evgeny N, Imyanitov, Marc, Tischkowitz, Ramunas, Janavicius, Esther M, John, Ava, Kwong, Orland, Diez, Judith, Balmaña, Rosa B, Barkardottir, Banu K, Arun, Gad, Rennert, Soo-Hwang, Teo, Patricia A, Ganz, Ian, Campbell, Annemarie H, van der Hout, Carolien H M, van Deurzen, Caroline, Seynaeve, Encarna B, Gómez Garcia, Flora E, van Leeuwen, Hanne E J, Meijers-Heijboer, Johannes J P, Gille, Margreet G E M, Ausems, Marinus J, Blok, Marjolijn J L, Ligtenberg, Matti A, Rookus, Peter, Devilee, Senno, Verhoef, Theo A M, van Os, Juul T, Wijnen, Debra, Frost, Steve, Ellis, Elena, Fineberg, Radka, Platte, D Gareth, Evans, Louise, Izatt, Rosalind A, Eeles, Julian, Adlard, Diana M, Eccles, Jackie, Cook, Carole, Brewer, Fiona, Douglas, Shirley, Hodgson, Patrick J, Morrison, Lucy E, Side, Alan, Donaldson, Catherine, Houghton, Mark T, Rogers, Huw, Dorkins, Jacqueline, Eason, Helen, Gregory, Emma, McCann, Alex, Murray, Alain, Calender, Agnès, Hardouin, Pascaline, Berthet, Capucine, Delnatte, Catherine, Nogues, Christine, Lasset, Claude, Houdayer, Dominique, Leroux, Etienne, Rouleau, Fabienne, Prieur, Francesca, Damiola, Hagay, Sobol, Isabelle, Coupier, Laurence, Venat-Bouvet, Laurent, Castera, Marion, Gauthier-Villars, Mélanie, Léoné, Pascal, Pujol, Sylvie, Mazoyer, Yves-Jean, Bignon, Elżbieta, Złowocka-Perłowska, Jacek, Gronwald, Jan, Lubinski, Katarzyna, Durda, Katarzyna, Jaworska, Tomasz, Huzarski, Amanda B, Spurdle, Alessandra, Viel, Bernard, Peissel, Bernardo, Bonanni, Giulia, Melloni, Laura, Ottini, Laura, Papi, Liliana, Varesco, Maria Grazia, Tibiletti, Paolo, Peterlongo, Sara, Volorio, Siranoush, Manoukian, Valeria, Pensotti, Norbert, Arnold, Christoph, Engel, Helmut, Deissler, Dorothea, Gadzicki, Andrea, Gehrig, Karin, Kast, Kerstin, Rhiem, Alfons, Meindl, Dieter, Niederacher, Nina, Ditsch, Hansjoerg, Plendl, Sabine, Preisler-Adams, Stefanie, Engert, Christian, Sutter, Raymonda, Varon-Mateeva, Barbara, Wappenschmidt, Bernhard H F, Weber, Brita, Arver, Marie, Stenmark-Askmalm, Niklas, Loman, Richard, Rosenquist, Zakaria, Einbeigi, Katherine L, Nathanson, Timothy R, Rebbeck, Stephanie V, Blank, David E, Cohn, Gustavo C, Rodriguez, Laurie, Small, Michael, Friedlander, Victoria L, Bae-Jump, Anneliese, Fink-Retter, Christine, Rappaport, Daphne, Gschwantler-Kaulich, Georg, Pfeiler, Muy-Kheng, Tea, Noralane M, Lindor, Bella, Kaufman, Shani, Shimon Paluch, Yael, Laitman, Anne-Bine, Skytte, Anne-Marie, Gerdes, Inge Sokilde, Pedersen, Sanne Traasdahl, Moeller, Torben A, Kruse, Uffe Birk, Jensen, Joseph, Vijai, Kara, Sarrel, Mark, Robson, Noah, Kauff, Anna Marie, Mulligan, Gord, Glendon, Hilmi, Ozcelik, Bent, Ejlertsen, Finn C, Nielsen, Lars, Jønson, Mette K, Andersen, Yuan Chun, Ding, Linda, Steele, Lenka, Foretova, Alex, Teulé, Conxi, Lazaro, Joan, Brunet, Miquel Angel, Pujana, Phuong L, Mai, Jennifer T, Loud, Christine, Walsh, Jenny, Lester, Sandra, Orsulic, Steven A, Narod, Josef, Herzog, Sharon R, Sand, Silvia, Tognazzo, Simona, Agata, Tibor, Vaszko, Joellen, Weaver, Alexandra V, Stavropoulou, Saundra S, Buys, Atocha, Romero, Miguel, de la Hoya, Kristiina, Aittomäki, Taru A, Muranen, Mercedes, Duran, Wendy K, Chung, Adriana, Lasa, Cecilia M, Dorfling, Alexander, Miron, Javier, Benitez, Leigha, Senter, Dezheng, Huo, Salina B, Chan, Anna P, Sokolenko, Jocelyne, Chiquette, Laima, Tihomirova, Tara M, Friebel, Bjarni A, Agnarsson, Karen H, Lu, Flavio, Lejbkowicz, Paul A, James, Per, Hall, Alison M, Dunning, Daniel, Tessier, Julie, Cunningham, Susan L, Slager, Chen, Wang, Steven, Hart, Kristen, Stevens, Jacques, Simard, Tomi, Pastinen, Vernon S, Pankratz, Kenneth, Offit, Douglas F, Easton, Georgia, Chenevix-Trench, and Antonis C, Antoniou
Subjects: BRCA2 Protein, Ovarian Neoplasms, Heterozygote, endocrine system diseases, Genotype, BRCA1 Protein, Breast Neoplasms, Middle Aged, Prognosis, Polymorphism, Single Nucleotide, Risk Factors, Mutation, Humans, Medicine, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Biology, Genome-Wide Association Study, Research Article
Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Author Summary BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.
Published: 2012

50. Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing

Author: Juul T. Wijnen, Marc Tischkowitz, J Van den Ende, Eric Legius, S Willocx, Bruce Poppe, Kathleen Claes, N Swietek, M. Van Bockstal, Nelly Sabbaghian, K De Leeneer, P Schietecatte, G Michils, A. De Paepe, Marinus J. Blok, Bettina Blaumeiser, Katrien Storm, K Leunen, S De Brouwer, Gert Matthijs, Encarna B. Gomez-Garcia, C. J. van Asperen, UCL - (SLuc) Service d'anatomie pathologique, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, Genetica & Celbiologie, RS: CARIM School for Cardiovascular Diseases, and RS: GROW - School for Oncology and Reproduction
Subjects: Male, Cancer Research, DNA Mutational Analysis, Hereditary breast and ovarian cancer, Mutation, Missense, BRCA1/2-negative, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Breast cancer, Germline mutation, Gene Frequency, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Genetic Testing, Allele, Germline mutations, Allele frequency, Genetic Association Studies, Genetic testing, Genetics, Mutation, medicine.diagnostic_test, RAD51C, medicine.disease, Pedigree, DNA-Binding Proteins, Oncology, Hereditary Breast and Ovarian Cancer Syndrome, Female, Human medicine, Ovarian cancer
Abstract: Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in
Published: 2012

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

71 results on '"Marinus J. Blok"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources