← Back to cohort
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus
Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan P. Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton‐Culver, Volker Arndt, Banu Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rósa B. Barkardóttir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benı́tez, Andrew Berchuck, Maria Bisogna, Line Bjørge, Carl Blomqvist, William J. Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne‐Lise Børresen‐Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Bützow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldés, Ian Campbell, Rikki Cannioto, Jenny Chang‐Claude, Jocelyne Chiquette, Ji‐Yeob Choi, Kathleen Claes, Marie- Agnès Collonge-Rame, Alexandre Damette, Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sévenet, Michel Longy, Pascaline Berthet, Dominique Vaur, Laurent Castéra, Sandra Fert Ferrer, Yves‐Jean Bignon, Nancy Uhrhammer, Fanny Coron, Laurence Faivre, Amandine Baurand, Caroline Jacquot, Geoffrey Bertolone, Sarab Lizard, Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon, Jean‐Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Claude Adenis, Laurence Venat‐Bouvet, Mélanie Léone, Nadia Boutry‐Kryza, Alain Calender, Sophie Giraud, Carole Verny-Pierre, Christine Lasset, Valérie Bonadona, Laure Barjhoux, Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Isabelle Coupier, Pascal Pujol, Johanna Sokolowska, Myriam Bronner, Capucine Delnatte, Stéphane Bezieau, Véronique Mari, Marion Gauthier‐Villars, Bruno Buecher, Étienne Rouleau, Lisa Golmard, Virginie Moncoutier, Muriel Belotti, Antoine De Pauw, Camille Elan, Emmanuelle Fourme, Anne‐Marie Birot, Claire Saule, M Laurent, Claude Houdayer, Fabienne Lesueur, Noura Mebirouk, Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin, Fabienne Prieur, Marine Lebrun, Danièle Muller, Jean‐Pierre Fricker, Christine Toulas, Rosine Guimbaud, Laurence Gladieff, V. Feillel, Isabelle Mortemousque, Brigitte Bressac–de Paillerets, Olivier Caron, Marine Guillaud-Bataille, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka‐Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Dı́ez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Helen Gregory, Zosia Miedzybrodzka, Patrick J. Morrison, Alan Donaldson, Mark T. Rogers, Michael J. Kennedy, Mary Porteous, Angela Brady, Julian Barwell, Claire Foo, Fiona Lalloo, Lucy Side, Jacqueline Eason, Alex Henderson, Lisa Walker, Jackie Cook, Katie Snape, Alex Murray, Emma McCann, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lídia Feliubadaló, Jonine D. Figueroa, Dieter Flesch‐Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretová, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy E. Garber, Montserrat García‐Closas, Aleksandra Gentry‐Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, Anna González‐Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas van Overeem Hansen, Patricia Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, Matti A. Rookus, F.E. van Leeuwen, Lizet E. van der Kolk, Marjanka K. Schmidt, Nicola S. Russell, Jeffrey L. Lange, R. Wijnands, J. Margriet Collée, Maartje J. Hooning, Caroline Seynaeve, Carolien H. M. van Deurzen, Inge-Marie Obdeijn, Christi J. van Asperen, Rob A.�E.�M. Tollenaar, T. C. T. E. F. van Cronenburg, C. Marleen Kets, Margreet G.E.M. Ausems, Carmen C. van der Pol, Theo A.M. van Os, Quinten Waisfisz, Hanne Meijers‐Heijboer, E. Gómez, Jan C. Oosterwijk, M J E Mourits, Geertruida H. de Bock, Hans F. A. Vasen, Sabine Siesling, Janneke Verloop, Lucy Overbeek, Florian Heitz, Josef Herzog, Estrid Høgdall, Claus Høgdall, Frans B.L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, Stephen B. Fox, Judy Kirk, Geoffrey J. Lindeman, Melanie A. Price, David D.L. Bowtell, Anna DeFazio, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramūnas Janavičius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne K. Kjær, Julia A. Knight, Irene Konstantopoulou, Veli‐Matti Kosma, Vessela Kristensen, Jolanta Kupryjańczyk, Ava Kwong, Miguel de la Hoya, Yael Laitman, Diether Lambrechts, Nhu D. Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubiński, Siranoush Manoukian, Loı̈c Le Marchand, Sara Margolin, Frederik Marmé, Leon F.A.G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain A. McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Oláh, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David M. O’Malley, Irene Orlow, Nick Orr, Ana Osório, Sue K. Park, Celeste Leigh Pearce, Tanja Pejović, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Rita K. Schmutzler, Thomas A. Sellers, Mitul Shah, Chen‐Yang Shen, Xiao‐Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark‐Askmalm, Dominique Stoppa‐Lyonnet, Christian Sutter, Anthony J. Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo‐Hwang Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda E. Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine M. Vachon, Ans M.W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. van’t Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Shan Wang‐Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook‐Yee Yoon, Jyh‐Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Álvaro N.A. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D.P. Pharoah, Stacey L. Edwards, Georgia Chenevix‐Trench, Antonis C. Antoniou
Bibliographic record
VenueNature Communications · 2016
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicGenomics and Chromatin Dynamics
Canadian institutionsPublic Health OntarioMcGill UniversityUniversité LavalCentre hospitalier universitaire de QuébecMount Sinai HospitalLunenfeld-Tanenbaum Research InstituteUniversity Health NetworkRoyal Victoria HospitalUniversity of Toronto
FundersMedical Research and Materiel CommandJonsson Comprehensive Cancer CenterNIH Office of the DirectorNational Cancer InstituteEuropean Regional Development FundNorway GrantsInstituto de Salud Carlos IIICancer Council NSWCancer Council VictoriaCancer Center, University of KansasUniversity of California, San FranciscoNational Institutes of Healthlékařská fakulta Univerzity KarlovyInstitut Català de la SalutDeutschen Konsortium für Translationale KrebsforschungLiga Portuguesa Contra o CancroUniversität UlmMinistero dello Sviluppo EconomicoUppsala UniversitetNational Health and Medical Research CouncilDeutsche KrebshilfeRoyal Marsden NHS Foundation TrustSahlgrenska UniversitetssjukhusetCancer Institute NSWMedizinischen Hochschule HannoverNational Medical Research CouncilNorges ForskningsrådCancer Council South AustraliaIstituto Oncologico VenetoMemorial Sloan-Kettering Cancer CenterKreftforeningenInstitut National Du CancerCancer Council QueenslandOak FoundationLeids Universitair Medisch CentrumCanadian Institutes of Health ResearchEuropean CommissionLietuvos Mokslo TarybaHelse VestKuopion Yliopistollinen SairaalaIstituto Toscano TumoriUniversitätsklinikum Hamburg-EppendorfRoswell Park Cancer InstituteDr. Ralph and Marian Falk Medical Research TrustIsrael Cancer AssociationMinistério da Ciência, Tecnologia e InovaçãoGeneral Secretariat for Research and TechnologyDeutsche Gesetzliche UnfallversicherungNederlandse Organisatie voor Wetenschappelijk OnderzoekMinistero della SaluteUniversity of Southern CaliforniaCancerfondenAcademy of FinlandKementerian Sains, Teknologi dan InovasiUniversitair Ziekenhuis GentRobert Bosch StiftungSingapore Eye Research InstituteHungarian Scientific Research FundCancer Association of South AfricaAmerican Cancer SocietyCancer AustraliaCalifornia Breast Cancer Research ProgramUniverzita Karlova v PrazeMcGill UniversityGeneralitat de CatalunyaKing's College LondonImperial College LondonCancer Research UKWorkSafeBCOhio State UniversityCanadian Breast Cancer Research AllianceWorld Health OrganizationNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungFrancis Crick InstituteMcGill University Health CentreDavid F. and Margaret T. Grohne Family FoundationUniversity of CambridgeFred C. and Katherine B. Andersen FoundationHelsingin ja Uudenmaan SairaanhoitopiiriCalifornia Department of Public HealthKræftens BekæmpelseKansas Bioscience AuthorityRutgers Cancer Institute of New JerseyMinistère du Développement Économique, de l’Innovation et de l’ExportationLon V. Smith FoundationGeorgetown UniversityCancer Council TasmaniaItä-Suomen YliopistoFox Chase Cancer CenterKWF KankerbestrijdingBiomedical Research CouncilClalit Health ServicesDeutsches KrebsforschungszentrumBreast Cancer Research FoundationAgency for Science, Technology and ResearchUniversity of ChicagoNRG OncologyWellcome TrustFondation du cancer du sein du QuébecUniversiteit GentNational Breast Cancer FoundationEuropean Social FundMedical Research CouncilMayo Foundation for Medical Education and ResearchAssociazione Italiana per la Ricerca sul CancroMinistry of Public HealthBeckman Research Institute, City of HopeNIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchJess and Mildred Fisher Center for Familial Cancer ResearchOregon Health and Science UniversityUmeå UniversitetU.S. Department of Health and Human ServicesU.S. ArmyLandspítali HáskólasjúkrahúsMinisterio de Economía y CompetitividadOvarian Cancer Research FundRheinische Friedrich-Wilhelms-Universität BonnBreast Cancer Research TrustNational Institute for Health and Care ResearchUniversity of California, IrvineOulun YliopistoFisher Center for Alzheimer's Research FoundationBeth Israel Deaconess Medical CenterSusan G. Komen for the CureFonds Wetenschappelijk OnderzoekMinnesota Ovarian Cancer AllianceUniversity of PennsylvaniaSundhed og Sygdom, Det Frie Forskningsråd
KeywordsAlleleLocus (genetics)Ovarian cancerGeneticsBreast cancerBiologyGeneBioinformaticsMedicineCancer
Abstract
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3'-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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)0.000
metaresearch head score (Gemma)0.001
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: none
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.003
Threshold uncertainty score0.010
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.003 | 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 head0.016
GPT teacher head0.269
Teacher spread0.253 · 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
Citations96
Published2016
Admission routes2
Has abstractyes