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Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk
Jingjing Liu, Wendy J.C. Prager ‐ van der Smissen, J. Margriet Collée, Manjeet K. Bolla, Qin Wang, Kyriaki Michailidou, Joe Dennis, Thomas U. Ahearn, Kristiina Aittomäki, Christine B. Ambrosone, Irene L. Andrulis, Hoda Anton‐Culver, Natalia Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Annelie Augustinsson, Päivi Auvinen, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Leslie Bernstein, Natalia Bogdanova, Nadja Bogdanova-Markov, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Ignacio Briceño, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Qiuyin Cai, Hui Cai, Daniele Campa, Federico Canzian, Jose E. Castelao, Jenny Chang‐Claude, Stephen J. Chanock, Ji‐Yeob Choi, Melissa Christiaens, Christine L. Clarke, Kristine Kleivi Sahlberg, Anne‐Lise Børresen‐Dale, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Drageset Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E. Kiserud, Kristin V. Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, Tone F. Bathen, Elin Borgen, Britt Fritzman, Øystein Garred, Gry Aarum Geitvik, Solveig Hofvind, Anita Langerød, Ole Christian Lingjærde, Gunhild M. Mælandsmo, Hege G. Russnes, Helle Kristine Skjerven, Thérese Sørlie, Grethe I.G. Alnæs, Fergus J. Couch, Kamila Czene, Mary B. Daly, Peter Devilee, Isabel dos‐Santos‐Silva, Miriam Dwek, A. Heather Eliassen, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Lin Fritschi, Manuela Gago-Domínguez, Susan M. Gapstur, Montserrat García‐Closas, José Á. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mark S. Goldberg, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Patricia Harrington, Steven N. Hart, Mikael Hartman, Peter Hillemanns, John L. Hopper, Ming‐Feng Hou, David J. Hunter, Dezheng Huo, Deborah J. Marsh, Rodney J. Scott, Robert C. Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter T. Simpson, J. Dinny Graham, Mythily Sachchithananthan, Hidemi Ito, Motoki Iwasaki, Milena Jakimovska, Anna Jakubowska, Esther M. John, Rudolf Kaaks, Daehee Kang, Renske Keeman, Э. К. Хуснутдинова, Sung-Won Kim, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, Loı̈c Le Marchand, Jingmei Li, Annika Lindblom, Artitaya Lophatananon, Robert Luben, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Shivaani Mariapun, Keitaro Matsuo, Tabea Maurer, Dimitrios Mavroudis, Usha Menon, Roger L. Milne, Kenneth Muir, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, Kenneth Offit, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Nick Orr, Sue K. Park, Paolo Peterlongo, Julian Peto, Dijana Plaseska‐Karanfilska, Nadège Presneau, Brigitte Rack, Rohini Rau‐Murthy, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Matthias Ruebner, Emmanouil Saloustros, Rita K. Schmutzler, Andreas Schneeweiß, Christopher J. Scott, Mitul Shah, Chen‐Yang Shen, Xiao-Ou Shu, Jacques Simard, Christof Sohn, Melissa C. Southey, John J. Spinelli, Rulla M. Tamimi, William Tapper, Soo‐Hwang Teo, Mary Beth Terry, Diana Torres, Thérèse Truong, Michael Untch, Celine M. Vachon, Christi J. van Asperen, Alicja Wolk, Taiki Yamaji, Wei Zheng, Argyrios Ziogas, Elad Ziv, Gabriela Torres-Mejı́a, Thilo Dörk, Anthony J. Swerdlow, Ute Hamann, Marjanka K. Schmidt, Alison M. Dunning, Paul D.P. Pharoah, Douglas F. Easton, Maartje J. Hooning, John W.M. Martens, Antoinette Hollestelle
Bibliographic record
VenueScientific Reports · 2020
Typearticle
Languageen
FieldMedicine
TopicCancer-related Molecular Pathways
Canadian institutionsUniversity of British ColumbiaUniversité LavalCentre hospitalier universitaire de QuébecMcGill UniversityUniversity Health NetworkUniversity of TorontoRoyal Victoria HospitalQueen's UniversityLunenfeld-Tanenbaum Research InstituteMount Sinai Hospital
FundersDivision of Cancer Epidemiology and Genetics, National Cancer InstituteFogarty International CenterNational Heart, Lung, and Blood InstituteBiomedical Research CouncilInstituto de Salud Carlos IIICancer Council Western AustraliaCancer Council VictoriaWorld Cancer Research FundMedical Research CouncilManchester Biomedical Research CentreCenter for Agroforestry, University of MissouriUniversity of California, IrvineHellenic Health FoundationFreistaat SachsenDeutschen Konsortium für Translationale KrebsforschungMinistry of Science and Higher Education of the Russian FederationMutuelle Générale de l'Education NationaleImperial Experimental Cancer Medicine CentreInstitut Gustave-RoussyMinistero dello Sviluppo EconomicoNational Health and Medical Research CouncilMinistry of Education, Science and TechnologyAcademia SinicaDeutsche KrebshilfeCancer Institute NSWMedizinischen Hochschule HannoverMemorial Sloan-Kettering Cancer CenterCentre International de Recherche sur le CancerKreftforeningenInstitut National Du CancerOak FoundationLeids Universitair Medisch CentrumInstituto Mexicano del Seguro SocialKWF KankerbestrijdingVetenskapsrådetNational Medical Research CouncilNorges ForskningsrådStockholms Läns LandstingUniversity of WestminsterLigue Contre le CancerCalifornia Department of Public HealthNational Research Foundation of KoreaAlexander von Humboldt-StiftungUniversity of Southern CaliforniaCancerfondenItä-Suomen YliopistoEberhard Karls Universität TübingenAmerican Cancer SocietyRussian Foundation for Basic ResearchKuopion Yliopistollinen SairaalaCancer Research InstituteUniversity of CreteInstitut National de la Santé et de la Recherche MédicaleWellcome TrustAgence Nationale de la RechercheJapan Agency for Medical Research and DevelopmentDeutsche Gesetzliche UnfallversicherungGentofte HospitalDeutsche ForschungsgemeinschaftNational Breast Cancer FoundationRosetrees TrustCanadian Institutes of Health ResearchEuropean CommissionStavros Niarchos FoundationFondation de FranceUniversity of UtahNational Research FoundationNIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchBreast Cancer CampaignNational Cancer InstituteEuropean Regional Development FundMinisterio de Sanidad, Servicios Sociales e IgualdadUniversity of CambridgeGovernment of CanadaAgence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du TravailSwedish Cancer FoundationPancreatic Cancer UKLon V. Smith FoundationMinistère du Développement Économique, de l’Innovation et de l’ExportationKorea Health Industry Development InstituteMcGill University Health CentreInstitute of Biomedical Sciences, Academia SinicaDavid F. and Margaret T. Grohne Family FoundationConsejo Nacional de Ciencia y TecnologíaSundhed og Sygdom, Det Frie ForskningsrådDeutsches KrebsforschungszentrumNational Research Foundation SingaporeCenters for Disease Control and PreventionNational Institute for Health and Care ResearchNational Institutes of HealthDivision of Cancer Prevention, National Cancer InstituteAssociazione Italiana per la Ricerca sul CancroKarolinska InstitutetHuntsman Cancer FoundationHarvard T.H. Chan School of Public HealthUniversity College LondonCancer Research UKFondation du cancer du sein du QuébecRheinische Friedrich-Wilhelms-Universität BonnBreast Cancer Research TrustAvon Foundation for WomenMinistry of Public HealthMinistry of Education, Culture, Sports, Science and TechnologyBeckman Research Institute, City of HopeRoyal Marsden NHS Foundation TrustUniversité LavalGenome CanadaBrigham and Women's HospitalRobert Bosch StiftungNational Cancer Research InstituteU.S. Department of Health and Human ServicesFonds Wetenschappelijk OnderzoekHuntsman Cancer InstituteServicio Gallego de SaludChina Scholarship CouncilMinisterio de Economía y CompetitividadBundesministerium für Bildung und ForschungOvarian Cancer Research FundMcGill UniversityBreast Cancer Research FoundationUniversitätsklinikum Hamburg-EppendorfXunta de GaliciaDr. Ralph and Marian Falk Medical Research TrustTaiwan BiobankInstituto de Seguriidad y Servicios Sociales de los Trabadores del Estado
KeywordsGermlineBreast cancerGermline mutationGeneticsBiologyCancerMedicineMutationOncologyGene
Abstract
In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
metaresearch head score (Codex)0.001
metaresearch head score (Gemma)0.000
Version: codex-gemma-dda1882f352aValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.672
Threshold uncertainty score0.934
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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 head0.017
GPT teacher head0.271
Teacher spread0.254 · 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 teacher head, not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
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
Citations6
Published2020
Admission routes2
Has abstractyes