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1. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

Author

Seçil Aksoy, Michael O. Woods, Heinric Williams, Bruno Buecher, Finlay A. Macrae, Lotte N. Krogh, Jay Qiu, Wan K.W. Juhari, Jan T. Lowery, Anne-Marie Gerdes, Magnus von Knebel Doeberitz, Luigi Ricciardiello, Karsten Schulmann, Jose Luis Soto, Kristina Lagerstedt-Robinson, Kiwamu Akagi, Raj Ramesar, Uffe Birk Jensen, Angel Alonso, Robert Hüneburg, Olivier Caron, Michel Longy, Jan Lubinski, Kate Green, Annabel Goodwin, D. Gareth Evans, Julie Wods, Leigha Senter, Matthew F. Kalady, Mark Clendenning, Barbara A. Leggett, Ravindran Ankathil, Swati G. Patel, Julian Barwell, Katherine M. Tucker, Grant Lee, Pascaline Berthet, Dawn M. Nixon, Sonia S. Kupfer, Naohiro Tomita, Susan Parry, Trinidad Caldés, Robert W. Haile, Edenir Inêz Palmero, Karin Alvarez, Cassandra B. Nichols, Mark A. Jenkins, N. Jewel Samadder, Loic LeMarchand, John Burn, Francisco Lopez, Rodney J. Scott, Pierre Laurent-Puig, Julie Arnold, Christina Therkildsen, Hans K. Schackert, Pilar Garre, Reinhard Buettner, Adriana Della Valle, Patricia Esperon, Wolff Schmiegel, Karl Heinimann, Inge Bernstein, Matthias Kloor, Nicoline Hoogerbrugge, Rui Manuel Reis, Fränzel J.B. Van Duijnhoven, Christoph Engel, Mohd Nizam Zahary, Sylviane Olschwang, Sapna Syngal, Valérie Bonadona, Nicholas Pachter, Matilde Navarro, Albert de la Chapelle, Beate Betz, Jukka-Pekka Mecklin, Catherine Noguès, Elena M. Stoffel, Toni T. Seppälä, Chrystelle Colas, Anneke Lucassen, Allan D. Spigelman, Youenn Drouet, Elisa J. Cops, Uri Ladabaum, Steve Thibodeau, Jeffrey N. Weitzel, Fiona Lalloo, Patrick J. Morrison, Maurizio Genuardi, Kohji Tanakaya, Patrick M. Lynch, Frederik J. Hes, William D. Foulkes, Carmen Guillén-Ponce, Jenny von Salomé, Emilia Rogoża-Janiszewska, Andrew Latchford, John L. Hopper, Carrie Snyder, Verónica Barca-Tierno, Gabriela Möslein, Lauren M. Gima, Melissa C. Southey, Paul A. James, Marion Dhooge, Claudia Perne, Steven Gallinger, Heather Hampel, Amanda B. Spurdle, Ingrid Winship, Emmanuelle Fourme, Rish K. Pai, Daniela Turchetti, Marta Pineda, Jürgen Weitz, James Hill, Daniel D. Buchanan, Carlos A. Vaccaro, Noralane M. Lindor, Rachel Pearlman, Pål Møller, Christian P. Strassburg, Jane C. Figueiredo, Aída Falcón de Vargas, Silke Zachariae, Karolin Bucksch, Joanne Ngeow, Silke Redler, Henrik Okkels, Maija R.J. Kohonen-Corish, Hans F. A. Vasen, Verena Steinke-Lange, Roselyne Guimbaud, Deepak Vangala, Isabelle Coupier, Nils Rahner, Berrin Tunca, Sanne W. Bajwa-ten Broeke, Niels de Wind, Sophie Lejeune, José Gaston Guillem, Karin Wadt, Polly A. Newcomb, Elke Holinski-Feder, Florencia Neffa, Rodrigo Santa Cruz Guindalini, Paul E. Wise, Julian R. Sampson, Graham Casey, Lene Juel Rasmussen, Rolf H. Sijmons, Tadeusz Dębniak, Ann-Sofie Backman, Joji Utsunomiya, Melyssa Aronson, Aung Ko Win, Yves-Jean Bignon, Judy W. C. Ho, Robyn L. Ward, Mev Dominguez-Valentin, Karolina Malińska, Elizabeth E. Half, John-Paul Plazzer, Marjolijn J. L. Ligtenberg, Rachel Austin, Nicola K. Poplawski, Marcia Cruz-Correa, Nagahide Matsubara, Charlotte Kvist Lautrup, Thomas Hansen, Tatsuro Yamaguchi, Thomas John, David J. Amor, Ilana Solomon, Yun-Hee Choi, Meghan J. van Wanzeele, Rakefet Shtoyerman, Vanessa Huntley, Maartje Nielsen, Deborah Neklason, Kevin J. Monahan, Gülçin Tezcan, Stefan Aretz, Talya Boisjoli, Sophie Giraud, Thierry Frebourg, Christophe Rosty, Heike Görgens, Lone Sunde, Allyson Templeton, Jacob Nattermann, Mala Pande, Joan Brunet, Nancy Uhrhammer, James M. Church, Florencia Spirandelli, Laurent Briollais, James G. Dowty, Jeanette C. Reece, Rachel Susman, Fay Kastrinos, Kirsi Pylvänäinen, Gabriel Capellá, Helène Schuster, Min H. Chew, Markus Loeffler, Christine Lasset, Michael J. Hall, Capuccine Delnatte, Floor A. Duijkers, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Digital Precision Cancer Medicine (iCAN), ATG - Applied Tumor Genomics, HUS Abdominal Center, Clinical sciences, Medical Genetics, Win A.K., Dowty J.G., Reece J.C., Lee G., Templeton A.S., Plazzer J.-P., Buchanan D.D., Akagi K., Aksoy S., Alonso A., Alvarez K., Amor D.J., Ankathil R., Aretz S., Arnold J.L., Aronson M., Austin R., Backman A.-S., Bajwa-ten Broeke S.W., Barca-Tierno V., Barwell J., Bernstein I., Berthet P., Betz B., Bignon Y.-J., Boisjoli T., Bonadona V., Briollais L., Brunet J., Bucksch K., Buecher B., Buettner R., Burn J., Caldes T., Capella G., Caron O., Casey G., Chew M.H., Choi Y.-H., Church J., Clendenning M., Colas C., Cops E.J., Coupier I., Cruz-Correa M., de la Chapelle A., de Wind N., Debniak T., Della Valle A., Delnatte C., Dhooge M., Dominguez-Valentin M., Drouet Y., Duijkers F.A., Engel C., Esperon P., Evans D.G., Falcon de Vargas A., Figueiredo J.C., Foulkes W., Fourme E., Frebourg T., Gallinger S., Garre P., Genuardi M., Gerdes A.-M., Gima L.M., Giraud S., Goodwin A., Gorgens H., Green K., Guillem J., Guillen-Ponce C., Guimbaud R., Guindalini R.S.C., Half E.E., Hall M.J., Hampel H., Hansen T.V.O., Heinimann K., Hes F.J., Hill J., Ho J.W.C., Holinski-Feder E., Hoogerbrugge N., Huneburg R., Huntley V., James P.A., Jensen U.B., John T., Juhari W.K.W., Kalady M., Kastrinos F., Kloor M., Kohonen-Corish M.R., Krogh L.N., Kupfer S.S., Ladabaum U., Lagerstedt-Robinson K., Lalloo F., Lasset C., Latchford A., Laurent-Puig P., Lautrup C.K., Leggett B.A., Lejeune S., LeMarchand L., Ligtenberg M., Lindor N., Loeffler M., Longy M., Lopez F., Lowery J., Lubinski J., Lucassen A.M., Lynch P.M., Malinska K., Matsubara N., Mecklin J.-P., Moller P., Monahan K., Morrison P.J., Nattermann J., Navarro M., Neffa F., Neklason D., Newcomb P.A., Ngeow J., Nichols C., Nielsen M., Nixon D.M., Nogues C., Okkels H., Olschwang S., Pachter N., Pai R.K., Palmero E.I., Pande M., Parry S., Patel S.G., Pearlman R., Perne C., Pineda M., Poplawski N.K., Pylvanainen K., Qiu J., Rahner N., Ramesar R., Rasmussen L.J., Redler S., Reis R.M., Ricciardiello L., Rogoza-Janiszewska E., Rosty C., Samadder N.J., Sampson J.R., Schackert H.K., Schmiegel W., Schulmann K., Schuster H., Scott R., Senter L., Seppala T.T., Shtoyerman R., Sijmons R.H., Snyder C., Solomon I.B., Soto J.L., Southey M.C., Spigelman A., Spirandelli F., Spurdle A.B., Steinke-Lange V., Stoffel E.M., Strassburg C.P., Sunde L., Susman R., Syngal S., Tanakaya K., Tezcan G., Therkildsen C., Thibodeau S., Tomita N., Tucker K.M., Tunca B., Turchetti D., Uhrhammer N., Utsunomiya J., Vaccaro C., van Duijnhoven F.J.B., van Wanzeele M.J., Vangala D.B., Vasen H.F.A., von Knebel Doeberitz M., von Salome J., Wadt K.A.W., Ward R.L., Weitz J., Weitzel J.N., Williams H., Winship I., Wise P.E., Wods J., Woods M.O., Yamaguchi T., Zachariae S., Zahary M.N., Hopper J.L., Haile R.W., Macrae F.A., Moslein G., and Jenkins M.A.

Subjects
0301 basic medicine, Proband, Oncology, Male, Heredity, DNA mismatch repair, [SDV]Life Sciences [q-bio], SUSCEPTIBILITY, Settore MED/03 - GENETICA MEDICA, 0302 clinical medicine, Residence Characteristics, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], PMS2, ComputingMilieux_MISCELLANEOUS, MLH1, Age Factors, Middle Aged, Penetrance, Lynch syndrome, 3. Good health, Pedigree, Phenotype, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, Female, Adult, medicine.medical_specialty, PENETRANCE, congenital, hereditary, and neonatal diseases and abnormalities, GENES, 3122 Cancers, colorectal cancer, BREAST, Risk Assessment, 03 medical and health sciences, Sex Factors, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Retrospective Studies, business.industry, MUTATIONS, Cancer, medicine.disease, digestive system diseases, MSH2, MSH6, MODEL, INDIVIDUALS, 030104 developmental biology, Lynch Syndrome, Gene-Environment Interaction, business
Abstract

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Published
2021
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2. Mutations of the Sonic Hedgehog Pathway Underlie Hypothalamic Hamartoma with Gelastic Epilepsy

Author

Nigel C. Jones, David Goldstein, Michael S. Hildebrand, John A. Damiano, John F. Kerrigan, Ezgi Ozturk, Benjamin W. Darbro, Erin L. Heinzen, Lynette G. Sadleir, Nicole G. Griffin, Heather J. Major, Rosemary Burgess, Jeremy L. Freeman, Richard J. Leventer, Andrew S. Allen, A. Simon Harvey, Ingrid E. Scheffer, Samuel F. Berkovic, and Elisa J. Cops

Subjects
Male, 0301 basic medicine, Candidate gene, animal structures, Hamartoma, Kruppel-Like Transcription Factors, Loss of Heterozygosity, Nerve Tissue Proteins, Zinc Finger Protein Gli2, 03 medical and health sciences, 0302 clinical medicine, Hypothalamic hamartoma, Zinc Finger Protein Gli3, Report, GLI2, GLI3, Genetics, Humans, Exome, Hedgehog Proteins, Genetics(clinical), Sonic hedgehog, Genetics (clinical), Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, biology, Wnt signaling pathway, Nuclear Proteins, CREB-Binding Protein, Hedgehog signaling pathway, 3. Good health, PRKACA, 030104 developmental biology, Mutation, embryonic structures, Cancer research, biology.protein, Female, Epilepsies, Partial, Hypothalamic Diseases, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Hypothalamic hamartoma (HH) with gelastic epilepsy is a well-recognized drug-resistant epilepsy syndrome of early life.(1) Surgical resection allows limited access to the small deep-seated lesions that cause the disease. Here, we report the results of a search for somatic mutations in paired hamartoma- and leukocyte-derived DNA samples from 38 individuals which we conducted by using whole-exome sequencing (WES), chromosomal microarray (CMA), and targeted resequencing (TRS) of candidate genes. Somatic mutations were identified in genes involving regulation of the sonic hedgehog (Shh) pathway in 14/38 individuals (37%). Three individuals had somatic mutations in PRKACA, which encodes a cAMP-dependent protein kinase that acts as a repressor protein in the Shh pathway, and four subjects had somatic mutations in GLI3, an Shh pathway gene associated with HH. In seven other individuals, we identified two recurrent and three single brain-tissue-specific, large copy-number or loss-of-heterozygosity (LOH) variants involving multiple Shh genes, as well as other genes without an obvious biological link to the Shh pathway. The Shh pathway genes in these large somatic lesions include the ligand itself (SHH and IHH), the receptor SMO, and several other Shh downstream pathway members, including CREBBP and GLI2. Taken together, our data implicate perturbation of the Shh pathway in at least 37% of individuals with the HH epilepsy syndrome, consistent with the concept of a developmental pathway brain disease.

Published
2016
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3. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Luigi Mori, Sara González, Elia Grau, Dieter Niederacher, Alexandra C. Kölbl, Ares Solanes, Cassandra B. Nichols, Marine Guillaud-Bataille, Ulrike Schoenwiese, Katherine L. Nathanson, Alfons Meindl, Ellen Honisch, Hans Ehrencrona, Ute Enders, Anke Waha, Trinidad Caldés, Inge Søkilde Pedersen, Ana Blanco, Emma Tudini, Conxi Lázaro, Paolo Radice, Torben A Kruse, María Concepción Alonso-Cerezo, Chantal Farra, Shan Wang-Gohrke, Wilko Weichert, Heli Nevanlinna, Setareh Moghadasi, Bernd Auber, Carla Bruzzone, Aliana Guerrieri-Gonzaga, Sabine Grill, Raymonda Varon, Nicolas Derive, Ana Vega, Nicolai Maass, Åke Borg, Cora M. Aalfs, Nadia Naldi, Silvia Iglesias, Kai Ren Ong, Encarna B. Gomez Garcia, Karl Hackmann, Emma R. Woodward, Norbert Arnold, David E. Goldgar, Bernard Peissel, Karolin Bucksch, Berardino Porfirio, Françoise Révillion, Angel Izquierdo, Isabell Witzel, Sebastian Wagner, Silke Zachariae, Elisa Alducci, Mads Thomassen, Jesús del Valle, Valentina Zampiga, Kerstin Rhiem, Lidia Moserle, Edenir Inêz Palmero, Maaike P.G. Vreeswijk, Christoph Mundhenke, Laura Papi, Alejandro Moles-Fernández, Paula Rofes, Ulrike Faust, Andrea Gehrig, Sandrine M. Caputo, Logan C. Walker, Fiona Lalloo, Ute Felbor, Joan Brunet, Henriette Roed Nielsen, Sean V. Tavtigian, Beatrice Bortesi, Thomas Hansen, Maria Grazia Tibiletti, Estela Carrasco, Lisa Wiesmüller, Viviana Gismondi, Sophie Krieger, Pedro Pérez-Segura, Esther Pohl-Rescigno, Emanuela Lucci-Cordisco, Barbara Wappenschmidt, Rui Manuel Reis, Gabriele Lorenzo Capone, Ileana Carnevali, Christi J. van Asperen, KCon Fab Investigators, Jochen Seggewiß, Rhiannon J. Walters, Irmgard Debatin, Susan M. Domchek, Marco Montagna, Francesca Gensini, Kristiina Aittomäki, Véronique Dutrannoy, Arcangela De Nicolo, Giulia Cagnoli, Elisa J. Cops, Henrique de Campos Reis Galvão, Giulia Cini, Barbara Riboli, Eva Tornero, Paul A. James, Judith Balmaña, Anne-Marie Gerdes, Heide Hellebrand, Miriam Fine, Mathias Stiller, Aldo Germani, Diana Eccles, Britta Blümcke, Dominique Stoppa-Lyonnet, Elena Leinert, Alexandra Lewis, Daniela Rivera, Verena Hübbel, Fergus J. Couch, Gunnar Schmidt, Katharina Keupp, Bernhard H. F. Weber, Tilman Heinrich, Mariarosaria Calvello, Michael Dean, Udo Jeschke, Vanessa Lattimore, Linda A.M. Janssen, Siranoush Manoukian, Eva Gross, Kelly J. Sullivan, Doris Steinemann, Susanne Ledig, Alessandra Viel, Christoph Engel, Ana Sánchez de Abajo, Nina Ditsch, Sandra Bonache, Maria A. Caligo, Katharina Pfeifer, Thomas Haaf, Christian Sutter, Eric Hahnen, Laura Matricardi, Marc Tischkowitz, Alex Teulé, Katherine M. Tucker, Jutta Giesecke, Silvia Tognazzo, Gemma Montalban, Carolina Gómez, Anders Kvist, Joanna Lim, Alison H. Trainer, Rachel Susman, Judit Horvath, Amanda B. Spurdle, Mirjam Larsen, Therese Törngren, Mónica Salinas, Nicholas Pachter, Rachel Austin, Nicola K. Poplawski, C Zeder-Göß, Juliane Ramser, Julia Ritter, Anne Sophie Vesper, Paola Concolino, D. Gareth Evans, Clemens R. Müller, Matilde Navarro, Sara Torres-Esquius, Claus R. Bartram, Laura Cortesi, Jacopo Azzollini, Marion Harris, Edward M. Clarke, Marion Kiechle, Lídia Feliubadaló, Almuth Caliebe, Karen N. Herold, Charlotte Kvist Lautrup, Anne S. Quante, Gardenia Vargas-Parra, Michael T. Parsons, Pietro Cavalli, Hongyan Li, Rodrigo Augusto Depieri Michelli, Irene Feroce, Achim Wöckel, Kerstin Wieland, Silke Kaulfuß, Soo Hwang Teo, Angela Velasco, Capucine Delnatte, Marta Pineda, Marion van Mackelenbergh, Eva Montes, Angela Toss, Rita K. Schmutzler, William D. Foulkes, Alvaro N.A. Monteiro, Jan Hauke, Monica Marabelli, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Esther Darder, Simona Agata, Amanda E. Toland, Bernardo Bonanni, Liliana Varesco, Orland Diez, Andreas Rump, Virginie Caux-Moncoutier, Gaetana Gambino, Markus Loeffler, Claude Houdayer, Elena Barbieri, Adrià López-Fernández, et. al., Universidade do Minho, QIMR Berghofer Medical Research Institute, Chinese Academy of Geological Sciences [Beijing] (CAGS), Ministry of Land and Resources (MLR), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Programa de Càncer Hereditari, Unitat de Diagnòstic Molecular, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Helsinki University Central Hospital, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Università degli Studi di Milano [Milano] (UNIMI), Medical Oncology Department, Vall d'Hebron University Hospital [Barcelona], Institute of Human Genetics, Universität Heidelberg [Heidelberg], Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC, CIBER-ER, Division of Cancer Prevention and Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Genetic Counseling and Hereditary Cancer Programme, Catalan Institute of Oncology, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Institut Curie [Paris], Programa de Consell Genètic en Càncer, Institut Català d'Oncologia, Girona-IdIBGi, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre René Gauducheau, CRLCC René Gauducheau, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Ludwig-Maximilians-Universität München (LMU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetics, University of Southampton, Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Genomic Medicine, University of Manchester [Manchester], Department of Medical Genetics, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Obstetrics and Gynaecology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institüt für Humangenetik [Würzburg], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institute of Chemistry [Budapest], Faculty of Sciences [Budapest], Eötvös Loránd University (ELTE)-Eötvös Loránd University (ELTE), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universitaet, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Department of Oncology, Lund University [Lund]-Clinical Sciences, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Institute for Medical Informatics, Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, University Medical Center Kiel, Department of Obstetrics and Gynecology, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Biochemistry, Section of Molecular Diagnostics, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Institute of Cell and Molecular Pathology, Medizinische Hochschule Hannover (MHH), University of California [Santa Cruz] (UCSC), University of California, Heidelberg University Hospital [Heidelberg], International Agency for Cancer Research (IACR), Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología-IDIBELL, L'Hospitalet, Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, CIBER de Enfermedades Raras (CIBERER), Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, University of Otago [Dunedin, Nouvelle-Zélande], Institute of Pathology, Department of Gynecology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), King‘s College London, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, University Management, University of Helsinki, Università degli Studi di Milano = University of Milan (UNIMI), Universität Heidelberg [Heidelberg] = Heidelberg University, Department of Genetics and Pathology, Uppsala University, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Julius-Maximilians-Universität Würzburg (JMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Firenze = University of Florence (UniFI), Université de Lille-UNICANCER-Université de Lille-UNICANCER, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Universität Leipzig, University of Cologne, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica

Subjects
Male, Multifactorial Inheritance, BRCA1, BRCA2, classification, clinical, multifactorial, quantitative, uncertain significance, variant, Alternative Splicing, BRCA1 Protein, BRCA2 Protein, Computational Biology, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Neoplasms, Mutation, Missense, Medicina Básica [Ciências Médicas], Settore MED/03 - GENETICA MEDICA, GUIDELINES, Genetic analysis, CLINGEN, SEQUENCE VARIANTS, Missense mutation, FUNCTIONAL ASSAYS, Genetics (clinical), BRCA1, BRCA2, quantitative, clinical, classification, multifactorial, variant, uncertain significance, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, SPLICING ANALYSIS, OVARIAN, BRCA2 Protein/genetics, 3. Good health, ddc, Mutation (genetic algorithm), Ciências Médicas::Medicina Básica, Medical genetics, Special Articles, medicine.medical_specialty, Posterior probability, Population, Computational biology, Biology, INTEGRATED EVALUATION, 03 medical and health sciences, Special Article, medicine, Genetics, BREAST-CANCER, Genetic variability, ddc:610, education, 030304 developmental biology, Tumors, Science & Technology, Proteins, Computational Biology/methods, RISKS, Mutation, BRCA1 Protein/genetics, 3111 Biomedicine, Missense, Proteïnes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genètica, Neoplasms/diagnosis
Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis

Published
2019
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4. The tissue-type plasminogen activator–plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans

Author

Jeffrey V. Rosenfeld, Catriona McLean, Rime Madani, Maria Daglas, Cristina Morganti-Kossmann, Andre L. Samson, Elisa J. Cops, Jean-Dominique Vassalli, Simone A. Beckham, Maithili Sashindranath, Daniel A. Lawrence, Adam Galle, Roxann Freeman, Enming J. Su, Eunice Sales, and Robert L. Medcalf

Subjects
Adult, Male, Proteases, Pathology, medicine.medical_specialty, Plasmin, medicine.medical_treatment, Matrix Metalloproteinase Inhibitors, Serpin, Biology, Tissue plasminogen activator, Capillary Permeability, Mice, chemistry.chemical_compound, Neuroserpin, Albumins, Plasminogen Activator Inhibitor 1, Fibrinolysis, medicine, Animals, Humans, Aged, Injections, Intraventricular, Aged, 80 and over, Dose-Response Relationship, Drug, Brain, Original Articles, Recovery of Function, Middle Aged, Matrix Metalloproteinases, Mice, Inbred C57BL, Disease Models, Animal, chemistry, Brain Injuries, Tissue Plasminogen Activator, Plasminogen activator inhibitor-1, Cancer research, Neurology (clinical), Plasminogen activator, medicine.drug
Abstract

The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma.

Published
2012
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5. Antiproliferative actions of the synthetic androgen, mibolerone, in breast cancer cells are mediated by both androgen and progesterone receptors

Author

Elisa J. Cops, Stephen N. Birrell, Wayne D. Tilley, Tina Bianco-Miotto, Lisa M. Butler, Nicole L. Moore, and Christine L. Clarke

Subjects
medicine.medical_specialty, medicine.drug_class, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Drug Evaluation, Preclinical, Breast Neoplasms, Medroxyprogesterone Acetate, Biology, urologic and male genital diseases, Biochemistry, Endocrinology, Internal medicine, Progesterone receptor, Tumor Cells, Cultured, medicine, Humans, Nandrolone, Mibolerone, Medroxyprogesterone acetate, Testosterone Congeners, Molecular Biology, Testosterone, Cell Proliferation, Estradiol, Dihydrotestosterone, Cell Biology, Androgen, Androgen receptor, Receptors, Androgen, Androgens, Molecular Medicine, Progestins, Receptors, Progesterone, Progestin, medicine.drug
Abstract

Androgen signaling, mediated by the androgen receptor (AR), is a critical factor influencing growth of normal and malignant breast cells. Given the increasing use of exogenous androgens in women, a better understanding of androgen action in the breast is essential. This study compared the effects of 5α-dihydrotestosterone (DHT) and a synthetic androgen, mibolerone, on estradiol (E2)-induced proliferation of breast cancer cells. DHT modestly inhibited E2-induced proliferation and mibolerone significantly inhibited proliferation in T-47D cells. The effects of both androgens could be reversed by an AR antagonist, suggesting that their actions were mediated, in part, by AR. Whereas high physiological doses (10–100 nM) of DHT reduced E2-mediated induction of the estrogen-regulated gene progesterone receptor (PR) to basal levels, mibolerone at lower doses (1 nM) eliminated PR expression, suggesting that mibolerone may also act via the PR. In the AR positive, PR-negative MCF-7 cells, mibolerone had modest effects on E2-induced proliferation, but was a potent inhibitor of proliferation in the AR positive, PR positive MCF-7M11 PRA cells. The effects of mibolerone in breast cancer cells were similar to those of the progestin, medroxyprogesterone acetate. Our results demonstrate that mibolerone can have both androgenic and progestagenic actions in breast cancer cells.

Published
2008
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6. Decreased Androgen Receptor Levels and Receptor Function in Breast Cancer Contribute to the Failure of Response to Medroxyprogesterone Acetate

Author

Nicole L. Moore, Wayne D. Tilley, Jacqueline M. Bentel, Miao Yang, Henry A. Simila, Carmella Ricciardelli, David J. Horsfall, Amelia A. Peters, Stephen N. Birrell, Elisa J. Cops, Tina Bianco-Miotto, Grant Buchanan, Jonathan M. Harris, Lisa M. Butler, and Katrina Ramsay

Subjects
Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Protein Conformation, Medroxyprogesterone, Estrogen receptor, Breast Neoplasms, Medroxyprogesterone Acetate, Gene mutation, Biology, Radioligand Assay, Cell Line, Tumor, Internal medicine, Chlorocebus aethiops, Progesterone receptor, medicine, Animals, Humans, Protein Isoforms, Receptor, Immunohistochemistry, Postmenopause, Androgen receptor, Endocrinology, Receptors, Estrogen, Oncology, Drug Resistance, Neoplasm, Receptors, Androgen, Dihydrotestosterone, COS Cells, Mutation, Female, Immunostaining, Signal Transduction, medicine.drug
Abstract

Previously, we reported that androgen receptor (AR), but not estrogen receptor (ER) or progesterone receptor (PR), is predictive of response to the synthetic progestin, medroxyprogesterone acetate (MPA), in a cohort of 83 patients with metastatic breast cancer. To further investigate the role of AR in determining response to MPA in this cohort, we analyzed AR levels by immunohistochemistry with two discrete antisera directed at either the NH2 or the COOH termini of the receptor. Compared with tumors that responded to MPA (n = 31), there was a significant decrease in the intensity and extent of AR immunoreactivity with both AR antisera in tumors from nonresponders (n = 52). Whereas only a single AR immunostaining pattern was detected in responders to MPA, reflecting concordance of immunoreactivity with the two AR antisera, tumors from nonresponders exhibited four distinct AR immunostaining patterns: (a) concordance with the two antibodies (31%), (b) staining only with the COOH-terminal antibody (33%), (c) staining only with the NH2-terminal antibody (22%), or (d) no immunoreactivity with either NH2- or COOH-terminal antibody (14%). DNA sequencing and functional analysis identified inactivating missense gene mutations in the ligand-binding domain of the AR in tumors from two of nine nonresponders positive with the NH2-terminal AR antisera but negative for COOH-terminal immunoreactivity and lacking specific, high-affinity dihydrotestosterone binding in tumor cytosol fractions. Tumors with more AR than the median level (37 fmol/mg protein) had significantly lower levels of PR (30 fmol/mg protein) than tumors with low AR (PR; 127 fmol/mg protein) despite comparable levels of ER. Ligand-dependent activation of the AR in human T47D and MCF-7 breast cancer cells resulted in inhibition of estradiol-stimulated cell proliferation and a reduction in the capacity of the ER to induce expression of the PR. These effects could be reversed using a specific AR antisense oligonucleotide. Increasing the ratio of AR to ER resulted in a greater androgen-dependent inhibition of ER function. Collectively, these data suggest that reduced levels of AR or impaired AR function contribute to the failure of MPA therapy potentially due to abrogation of the inhibitory effect of AR on ER signaling.

Published
2005
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