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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
Gisella Figlioli, Massimo Bogliolo, Irene Catucci, Laura Caleca, Sandra Viz-Lasheras, Roser Pujol, Johanna I. Kiiski, Taru Muranen, Daniel R. Barnes, Joe Dennis, Kyriaki Michailidou, Manjeet K. Bolla, Goska Leslie, Cora M. Aalfs, Robert Baxter, Stephen Braye, Jane Carpenter, Jane E. Dahlstrom, John Forbes, C. Soon Lee, Deborah J. Marsh, Adrienne Morey, Nirmala Pathmanathan, Rodney Scott, Peter Simpson, Allan Spigelman, Nicholas Wilcken, Desmond Yip, Nikolajs Zeps, Muriel A. Adank, Julian Adlard, Simona Agata, Karen Cadoo, Bjarni A. Agnarsson, Thomas Ahearn, Kristiina Aittomäki, Christine B. Ambrosone, Lesley Andrews, Hoda Anton-Culver, Natalia Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu Arun, Ella Asseryanis, Bernd Auber, Päivi Auvinen, Jacopo Azzollini, Judith Balmañà, Rósa B. Barkardóttir, Daniel Barrowdale, Julian Barwell, Laura E. Beane Freeman, Charles Joly Beauparlant, Matthias W. 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Bibliographic record
Venuenpj Breast Cancer · 2019
Typearticle
Languageen
FieldBiochemistry, Genetics and Molecular Biology
TopicDNA Repair Mechanisms
Canadian institutionsAmgen (Canada)University of British ColumbiaUniversity of TorontoRoyal Victoria HospitalLunenfeld-Tanenbaum Research InstituteMount Sinai HospitalUniversité LavalBC Cancer AgencyCentre hospitalier universitaire de QuébecMcGill UniversityQueen's University
FundersDivision of Cancer Epidemiology and Genetics, National Cancer InstituteNIH Office of the DirectorServicio Gallego de SaludNational Cancer InstituteEuropean Regional Development FundCancer Council VictoriaMedical Research CouncilEuropean CommissionLietuvos Mokslo TarybaCanadian Institutes of Health ResearchImperial Experimental Cancer Medicine CentreDivision of Cancer Prevention, National Cancer InstituteNational Institutes of HealthFreistaat SachsenCentro de Investigación Biomédica en Red de CáncerFederal Agency for Scientific OrganizationsNational Institute of General Medical SciencesDeutschen Konsortium für Translationale KrebsforschungKWF KankerbestrijdingFox Chase Cancer CenterMinistero dello Sviluppo EconomicoJewish General HospitalNational Institute for Health and Care ResearchCenters for Disease Control and PreventionMemorial Sloan-Kettering Cancer CenterIstituto Oncologico VenetoInstitut National Du CancerNational Health and Medical Research CouncilDeutsche KrebshilfeFondazione Umberto VeronesiVetenskapsrådetStockholms Läns LandstingKuopion Yliopistollinen SairaalaMinistero della SaluteMcGill UniversityGeneralitat de CatalunyaCancer Center, University of KansasUniversity of Southern CaliforniaCancerfondenLandspítali HáskólasjúkrahúsMinisterio de Economía y CompetitividadNational Center for Advancing Translational SciencesBundesministerium für Bildung und ForschungItä-Suomen YliopistoEberhard Karls Universität TübingenFondation ARC pour la Recherche sur le CancerAmerican Cancer SocietyCancer AustraliaRussian Foundation for Basic ResearchDeutsche Gesetzliche UnfallversicherungNederlandse Organisatie voor Wetenschappelijk OnderzoekDeutsche ForschungsgemeinschaftDeutscher Akademischer AustauschdienstProgramme Grants for Applied ResearchRobert Bosch StiftungAssociazione Italiana per la Ricerca sul CancroKarolinska InstitutetHungarian Scientific Research FundHarvard T.H. Chan School of Public HealthCancer Association of South AfricaRoyal Marsden NHS Foundation TrustInstitució Catalana de Recerca i Estudis AvançatsCentres de Recerca de CatalunyaUniversity of CambridgeNemzeti Kutatási Fejlesztési és Innovációs HivatalGovernment of CanadaGeorgetown UniversityBreast Cancer CampaignNIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer ResearchNational Breast Cancer FoundationNational Institute of Environmental Health SciencesSwedish Cancer FoundationMcGill University Health CentreUniversity of California, IrvineDavid F. and Margaret T. Grohne Family FoundationDeutsches KrebsforschungszentrumWorld Cancer Research FundHelsingin ja Uudenmaan SairaanhoitopiiriLon V. Smith FoundationMinistère du Développement Économique, de l’Innovation et de l’ExportationFundación Mutua MadrileñaBreast Cancer Research FoundationUniversity of ChicagoNRG OncologyFondation du cancer du sein du QuébecUniversitätsklinikum Hamburg-EppendorfDr. Ralph and Marian Falk Medical Research TrustKansas Bioscience AuthorityInstitut Català de la SalutUniversity of PennsylvaniaLiga Portuguesa Contra o CancroUniversity College LondonCancer Research UKBeckman Research Institute, City of HopeSusan G. Komen for the CureBeth Israel Deaconess Medical CenterGenome CanadaBrigham and Women's HospitalInstituto de Salud Carlos IIIOhio State UniversityUniversity of California, San FranciscoU.S. Department of Health and Human ServicesRheinische Friedrich-Wilhelms-Universität BonnOak FoundationFisher Center for Alzheimer's Research FoundationFanconi Anemia Research FundFonds Wetenschappelijk Onderzoek
KeywordsCHEK2Breast cancerPALB2Triple-negative breast cancerBiologyCancerOlaparibCancer researchGeneticsInternal medicineOncologyMedicineGermline mutationMutationGene
Abstract
Abstract Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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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)0.000
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: Observational
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.004
Threshold uncertainty score0.012
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.004 | 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 head0.004
GPT teacher head0.228
Teacher spread0.224 · 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".
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Citations46
Published2019
Admission routes2
Has abstractyes