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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas U. Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton‐Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heiko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Åke Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang‐Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen Claes, Christine L. Clarke, Ophélie Bertrand, Sandrine M. Caputo, Anaïs Dupré, Marine Le Mentec, Muriel Belotti, Bruno Buecher, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Claude Houdayer, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Mélanie Léone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud, Olivier Caron, Marine Guillaud-Bataille, Brigitte Bressac–de Paillerets, Yves- Jean Bignon, Nancy Uhrhammer, Christine Lasset, Valérie Bonadona, Pascaline Berthet, Dominique Vaur, Laurent Castéra, Cornel Popovici, Hagay Sobol, Violaine Bourdon, Audrey Remenieras, Catherine Noguès, Isabelle Coupier, Pascal Pujol, Aurélie Dumont, Françoise Révillion, Claude Adenis, Danièle Muller, Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy, Christine Toulas, Rosine Guimbaud, Laurence Gladieff, V. Feillel, Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon, Fanny Coron, Laurence Faivre, Amandine Baurand, Caroline Jacquot, Geoffrey Bertolone, Sarab Lizard, Fabienne Prieur, Marine Lebrun, Caroline Kientz, Sandra Fert Ferrer, Véronique Mari, Laurence Vénat-Bouvet, Capucine Delnatte, Stéphane Bézieau, Isabelle Mortemousque, Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin, Johanna Sokolowska, Myriam Bronner, Marie‐Agnès Collonge‐Rame, Alexandre Damette, Paul Gesta, Hakima Lallaoui, Jean Chiésa, Denise Molina-Gomes, Olivier Ingster, Helen Gregory, Zosia Miedzybrodzka, Patrick J. Morrison, Kai-Ren Ong, Alan Donaldson, Mark T. Rogers, Michael J. Kennedy, Mary Porteous, Carole Brewer, Rosemarie Davidson, Louise Izatt, Angela Brady, Julian Barwell, Julian Adlard, Claire Foo, Fiona Lalloo, Lucy Side, Jacqueline Eason, Alex Henderson, Lisa Walker, Rosalind A. Eeles, Jackie Cook, Katie Snape, Diana Eccles, Alex Murray, Emma McCann, Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Dı́ez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos‐Santos‐Silva, Alison M. Dunning, Miriam Dwek, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Domínguez, Susan M. Gapstur, Judy Garber, Vanesa García‐Barberán, Montserrat García‐Closas, José Á. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González‐Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, Stephen Fox, Ian Campbell, Amanda Spurdle, Anna de Fazio, Margaret Tassell, Judy Kirk, Geoffrey J. Lindeman, Melanie A. Price, Melissa C. Southey, Roger Milne, Sid Deb, David D.L. Bowtell, Annemieke H. van der Hout, Ans M.W. van den Ouweland, Arjen R. Mensenkamp, Carolien H. M. van Deurzen, Carolien M. Kets, Caroline Seynaeve, Christi J. van Asperen, Cora M. Aalfs, E. Gómez, Flora E. van Leeuwen, Geertruida H. de Bock, Hanne E. J. Meijers-Heijboer, Inge M. Obdeijn, J. J. P. Gille, Jan C. Oosterwijk, Juul Wijnen, Lizet E. van der Kolk, Maartje J. Hooning, Margreet G. E. M. Ausems, Marian J E Mourits, Marinus J. Blok, Matti A. Rookus, Rob B. van der Luijt, T. C. T. E. F. van Cronenburg, Carmen C. van der Pol, Nicola S. Russell, Sabine Siesling, Lucy Overbeek, R. Wijnands, Judith L. de Lange, Dinny Graham, Mythily Sachchithananthan, Deborah J. Marsh, Rodney J. Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter T. Simpson, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, R. Kaaks, Pooja Middha, Beth Y. Karlan, Renske Keeman, Э. К. Хуснутдинова, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, L. Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adrià López‐Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W.M. Martens, Noura Mebirouk, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osório, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Søkilde Pedersen, Beth N. Peshkin, Paolo Peterlongo, Julian Peto, Paul D.P. Pharoah, Kelly‐Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Hedy S. Rennert, Mark E. Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher G. Scott, Priyanka Sharma, Penny Soucy, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa‐Lyonnet, Anthony J. Swerdlow, Rulla M. Tamimi, William Tapper, Jack A. Taylor, Mary Beth Terry, Àlex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix‐Trench, Douglas F. Easton, Nadine Andrieu, Antonis C. Antoniou
Bibliographic record
VenueNature Communications · 2021
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicBRCA gene mutations in cancer
Canadian institutionsUniversity of British ColumbiaUniversité LavalCentre hospitalier universitaire de QuébecMcGill UniversityUniversity of TorontoRoyal Victoria HospitalQueen's UniversityLunenfeld-Tanenbaum Research InstituteMount Sinai Hospital
FundersDivision of Cancer Epidemiology and Genetics, National Cancer InstituteMedical Research and Materiel CommandNIH Office of the DirectorServicio Gallego de SaludInstituto de Salud Carlos IIICancer Council Western AustraliaCancer Council NSWCancer Council VictoriaWorld Cancer Research FundEuropean Social FundMedical Research CouncilCancer Center, University of KansasDivision of Cancer Prevention, National Cancer InstituteNational Institutes of HealthHellenic Health FoundationFreistaat SachsenCentro de Investigación Biomédica en Red de CáncerFederal Agency for Scientific OrganizationsNational Institute of General Medical SciencesDeutschen Konsortium für Translationale KrebsforschungUniversitätsklinikum Hamburg-EppendorfDr. Ralph and Marian Falk Medical Research TrustXunta de GaliciaMutuelle Générale de l'Education NationaleKWF KankerbestrijdingFox Chase Cancer CenterMinistero dello Sviluppo EconomicoCancer Council South AustraliaIstituto Oncologico VenetoMemorial Sloan-Kettering Cancer CenterCentre International de Recherche sur le CancerInstitut National Du CancerNational Health and Medical Research CouncilDeutsche KrebshilfeVetenskapsrådetNational Medical Research CouncilStockholms Läns LandstingKuopion Yliopistollinen SairaalaAssociazione Italiana per la Ricerca sul CancroKarolinska InstitutetMcGill UniversityGeneralitat de CatalunyaUniversity of Southern CaliforniaCancerfondenCancer Council TasmaniaItä-Suomen YliopistoEberhard Karls Universität TübingenAmerican Cancer SocietyCancer AustraliaRussian Foundation for Basic ResearchUniversity of CreteMinistero della SaluteInstitut National de la Santé et de la Recherche MédicaleDeutsche Gesetzliche UnfallversicherungNederlandse Organisatie voor Wetenschappelijk OnderzoekGentofte HospitalDeutsche ForschungsgemeinschaftRobert Bosch StiftungU.S. ArmyLigue Contre le CancerUniversity of WestminsterCanadian Institutes of Health ResearchEuropean CommissionCancer Institute NSWUniversity College LondonHospital de Câncer de BarretosNational Cancer InstituteEuropean Regional Development FundMinisterio de Sanidad, Servicios Sociales e IgualdadUniversity of CambridgeGovernment of CanadaUniversity of PennsylvaniaStavros Niarchos FoundationFondation de FranceGeorgetown UniversityBreast Cancer CampaignNIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchNational Breast Cancer FoundationAgence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du TravailNational Institute of Environmental Health SciencesSwedish Cancer FoundationUniversity of California, IrvineNewcastle UniversityDavid F. and Margaret T. Grohne Family FoundationSundhed og Sygdom, Det Frie ForskningsrådDeutsches KrebsforschungszentrumBreast Cancer Research FoundationMinistère du Développement Économique, de l’Innovation et de l’ExportationLon V. Smith FoundationFundación Mutua MadrileñaCalifornia Department of Public HealthGenome CanadaJewish General HospitalNational Institute for Health and Care ResearchUniversity of ChicagoNRG OncologyFondation du cancer du sein du QuébecCancer Research UKAmerican Breast Cancer FoundationBeckman Research Institute, City of HopeSusan G. Komen for the CureBeth Israel Deaconess Medical CenterFundación CellexFisher Center for Alzheimer's Research FoundationRheinische Friedrich-Wilhelms-Universität BonnUniversitair Medisch Centrum GroningenOak FoundationKansas Bioscience AuthorityInstitut Català de la SalutImperial Experimental Cancer Medicine CentreInstitut Gustave-RoussyOhio State UniversityRoyal Marsden NHS Foundation TrustUniversity of California, San FranciscoU.S. Department of Health and Human ServicesAgence Nationale de la RechercheMinisterio de Economía y CompetitividadNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungOvarian Cancer Research FundFonds Wetenschappelijk Onderzoek
KeywordsBreast cancerMutationGeneticsCancerMedicineBiologyOncologyGene
Abstract
Abstract Breast cancer (BC) risk forBRCA1andBRCA2mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases withBRCA1orBRCA2mutations. We identify robust novel associations for 2 variants with BC forBRCA1and 3 forBRCA2mutation carriers,P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 whereMADD,SP11andEIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores forBRCA1andBRCA2mutation carriers.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.005
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Observational · Consensus signal: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.006
Threshold uncertainty score0.015
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.020
GPT teacher head0.361
Teacher spread0.341 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designObservational
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations39
Published2021
Admission routes2
Has abstractyes