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Rare germline copy number variants (CNVs) and breast cancer risk

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cam.depositDate2021-12-20
cam.issuedOnline2022-01-18
cam.orpheus.successTue Feb 01 19:02:33 GMT 2022 - Embargo updated*
datacite.ispreviousversionof.handlehttps://www.repository.cam.ac.uk/items/2b82243d-43e7-4230-b627-9d60e6d98e63
dc.contributor.authorDennis, Joe
dc.contributor.authorTyrer, Jonathan
dc.contributor.authorWalker, Logan C
dc.contributor.authorMichailidou, Kyriaki
dc.contributor.authorDorling, Leila
dc.contributor.authorBolla, Manjeet K
dc.contributor.authorWang, Jean
dc.contributor.authorAhearn, Thomas U
dc.contributor.authorAndrulis, Irene L
dc.contributor.authorAnton-Culver, Hoda
dc.contributor.authorAntonenkova, Natalia N
dc.contributor.authorArndt, Volker
dc.contributor.authorAronson, Kristan J
dc.contributor.authorFreeman, Laura E Beane
dc.contributor.authorBeckmann, Matthias W
dc.contributor.authorBehrens, Sabine
dc.contributor.authorBenitez, Javier
dc.contributor.authorBermisheva, Marina
dc.contributor.authorBogdanova, Natalia V
dc.contributor.authorBojesen, Stig E
dc.contributor.authorBrenner, Hermann
dc.contributor.authorCastelao, Jose E
dc.contributor.authorChang-Claude, Jenny
dc.contributor.authorChenevix-Trench, Georgia
dc.contributor.authorClarke, Christine L
dc.contributor.authorKristensen, Vessela N
dc.contributor.authorSahlberg, Kristine K
dc.contributor.authorBørresen-Dale, Anne-Lise
dc.contributor.authorGram, Inger Torhild
dc.contributor.authorEngebråten, Olav
dc.contributor.authorNaume, Bjørn
dc.contributor.authorGeisler, Jürgen
dc.contributor.authorAlnæs, Grethe I Grenaker
dc.contributor.authorCollée, J Margriet
dc.contributor.authorLacey, James
dc.contributor.authorMartinez, Elena
dc.contributor.authorCouch, Fergus J
dc.contributor.authorCox, Angela
dc.contributor.authorCross, Simon S
dc.contributor.authorCzene, Kamila
dc.contributor.authorDevilee, Peter
dc.contributor.authorDörk, Thilo
dc.contributor.authorDossus, Laure
dc.contributor.authorEliassen, A Heather
dc.contributor.authorEriksson, Mikael
dc.contributor.authorEvans, D Gareth
dc.contributor.authorFasching, Peter A
dc.contributor.authorFigueroa, Jonine
dc.contributor.authorFletcher, Olivia
dc.contributor.authorFlyger, Henrik
dc.contributor.authorFritschi, Lin
dc.contributor.authorGabrielson, Marike
dc.contributor.authorGago-Dominguez, Manuela
dc.contributor.authorGarcía-Closas, Montserrat
dc.contributor.authorGiles, Graham G
dc.contributor.authorGonzález-Neira, Anna
dc.contributor.authorGuénel, Pascal
dc.contributor.authorHahnen, Eric
dc.contributor.authorHaiman, Christopher A
dc.contributor.authorHall, Per
dc.contributor.authorHollestelle, Antoinette
dc.contributor.authorHoppe, Reiner
dc.contributor.authorHopper, John L
dc.contributor.authorHowell, Anthony
dc.contributor.authorClarke, Christine
dc.contributor.authorCarpenter, Jane
dc.contributor.authorMarsh, Deborah
dc.contributor.authorScott, Rodney
dc.contributor.authorBaxter, Robert
dc.contributor.authorYip, Desmond
dc.contributor.authorDavis, Alison
dc.contributor.authorPathmanathan, Nirmala
dc.contributor.authorSimpson, Peter
dc.contributor.authorGraham, Dinny
dc.contributor.authorSachchithananthan, Mythily
dc.contributor.authorCampbell, Ian
dc.contributor.authorde Fazio, Anna
dc.contributor.authorFox, Stephen
dc.contributor.authorKirk, Judy
dc.contributor.authorLindeman, Geoff
dc.contributor.authorMilne, Roger
dc.contributor.authorSouthey, Melissa
dc.contributor.authorSpurdle, Amanda
dc.contributor.authorThorne, Heather
dc.contributor.authorJager, Agnes
dc.contributor.authorJakubowska, Anna
dc.contributor.authorJohn, Esther M
dc.contributor.authorJohnson, Nichola
dc.contributor.authorJones, Michael E
dc.contributor.authorJung, Audrey
dc.contributor.authorKaaks, Rudolf
dc.contributor.authorKeeman, Renske
dc.contributor.authorKhusnutdinova, Elza
dc.contributor.authorKitahara, Cari M
dc.contributor.authorKo, Yon-Dschun
dc.contributor.authorKosma, Veli-Matti
dc.contributor.authorKoutros, Stella
dc.contributor.authorKraft, Peter
dc.contributor.authorKristensen, Vessela N
dc.contributor.authorKubelka-Sabit, Katerina
dc.contributor.authorKurian, Allison W
dc.contributor.authorLacey, James V
dc.contributor.authorLambrechts, Diether
dc.contributor.authorLarson, Nicole L
dc.contributor.authorLinet, Martha
dc.contributor.authorOgrodniczak, Alicja
dc.contributor.authorMannermaa, Arto
dc.contributor.authorManoukian, Siranoush
dc.contributor.authorMargolin, Sara
dc.contributor.authorMavroudis, Dimitrios
dc.contributor.authorMilne, Roger L
dc.contributor.authorMuranen, Taru A
dc.contributor.authorMurphy, Rachel A
dc.contributor.authorNevanlinna, Heli
dc.contributor.authorOlson, Janet E
dc.contributor.authorOlsson, Håkan
dc.contributor.authorPark-Simon, Tjoung-Won
dc.contributor.authorPerou, Charles M
dc.contributor.authorPeterlongo, Paolo
dc.contributor.authorPlaseska-Karanfilska, Dijana
dc.contributor.authorPylkäs, Katri
dc.contributor.authorRennert, Gad
dc.contributor.authorSaloustros, Emmanouil
dc.contributor.authorSandler, Dale P
dc.contributor.authorSawyer, Elinor J
dc.contributor.authorSchmidt, Marjanka K
dc.contributor.authorSchmutzler, Rita K
dc.contributor.authorShibli, Rana
dc.contributor.authorSmeets, Ann
dc.contributor.authorSoucy, Penny
dc.contributor.authorSouthey, Melissa C
dc.contributor.authorSwerdlow, Anthony J
dc.contributor.authorTamimi, Rulla M
dc.contributor.authorTaylor, Jack A
dc.contributor.authorTeras, Lauren R
dc.contributor.authorTerry, Mary Beth
dc.contributor.authorTomlinson, Ian
dc.contributor.authorTroester, Melissa A
dc.contributor.authorTruong, Thérèse
dc.contributor.authorVachon, Celine M
dc.contributor.authorWendt, Camilla
dc.contributor.authorWinqvist, Robert
dc.contributor.authorWolk, Alicja
dc.contributor.authorYang, Xiaohong R
dc.contributor.authorZheng, Wei
dc.contributor.authorZiogas, Argyrios
dc.contributor.authorSimard, Jacques
dc.contributor.authorDunning, Alison
dc.contributor.authorPharoah, Paul
dc.contributor.authorEaston, Douglas
dc.contributor.orcidDennis, Joe [0000-0003-4591-1214]
dc.contributor.orcidTyrer, Jonathan [0000-0003-3724-4757]
dc.contributor.orcidWalker, Logan C [0000-0003-0018-3719]
dc.contributor.orcidMichailidou, Kyriaki [0000-0001-7065-1237]
dc.contributor.orcidWang, Jean [0000-0002-9139-0627]
dc.contributor.orcidAndrulis, Irene L [0000-0002-4226-6435]
dc.contributor.orcidArndt, Volker [0000-0001-9320-8684]
dc.contributor.orcidAronson, Kristan J [0000-0002-7865-7243]
dc.contributor.orcidBehrens, Sabine [0000-0002-9714-104X]
dc.contributor.orcidKristensen, Vessela N [0000-0001-5012-7438]
dc.contributor.orcidDörk, Thilo [0000-0002-9458-0282]
dc.contributor.orcidDossus, Laure [0000-0003-2716-5748]
dc.contributor.orcidFigueroa, Jonine [0000-0002-5100-623X]
dc.contributor.orcidFritschi, Lin [0000-0002-7692-3560]
dc.contributor.orcidGiles, Graham G [0000-0003-4946-9099]
dc.contributor.orcidHollestelle, Antoinette [0000-0003-1166-1966]
dc.contributor.orcidJakubowska, Anna [0000-0002-5650-0501]
dc.contributor.orcidJohnson, Nichola [0000-0002-8230-5662]
dc.contributor.orcidJones, Michael E [0000-0001-7479-3451]
dc.contributor.orcidKeeman, Renske [0000-0002-5452-9933]
dc.contributor.orcidKristensen, Vessela N [0000-0001-5012-7438]
dc.contributor.orcidLarson, Nicole L [0000-0002-2129-6934]
dc.contributor.orcidMilne, Roger L [0000-0001-5764-7268]
dc.contributor.orcidNevanlinna, Heli [0000-0002-0916-2976]
dc.contributor.orcidOlson, Janet E [0000-0003-4944-7789]
dc.contributor.orcidPeterlongo, Paolo [0000-0001-6951-6855]
dc.contributor.orcidPlaseska-Karanfilska, Dijana [0000-0001-8877-2416]
dc.contributor.orcidPylkäs, Katri [0000-0002-2449-0521]
dc.contributor.orcidRennert, Gad [0000-0002-8512-068X]
dc.contributor.orcidTomlinson, Ian [0000-0003-3037-1470]
dc.contributor.orcidTruong, Thérèse [0000-0002-2943-6786]
dc.contributor.orcidVachon, Celine M [0000-0002-1962-9322]
dc.contributor.orcidWolk, Alicja [0000-0001-7387-6845]
dc.contributor.orcidZiogas, Argyrios [0000-0003-4529-3727]
dc.contributor.orcidSimard, Jacques [0000-0001-6906-3390]
dc.contributor.orcidDunning, Alison [0000-0001-6651-7166]
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.date.accessioned2021-12-21T00:32:52Z
dc.date.available2021-12-21T00:32:52Z
dc.date.issued2022-12
dc.date.updated2021-12-20T12:28:09Z
dc.description.abstract<jats:title>Abstract</jats:title><jats:p>Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in <jats:italic>BRCA1</jats:italic> (<jats:italic>P</jats:italic> = 3.7E−18). Nine other genes were associated with a <jats:italic>p</jats:italic>-value &lt; 0.01 including known susceptibility genes <jats:italic>CHEK2</jats:italic> (<jats:italic>P</jats:italic> = 0.0008), <jats:italic>ATM</jats:italic> (<jats:italic>P</jats:italic> = 0.002) and <jats:italic>BRCA2</jats:italic> (<jats:italic>P</jats:italic> = 0.008). Outside the known genes we detected associations with <jats:italic>p</jats:italic>-values &lt; 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.</jats:p>
dc.identifier.doi10.17863/CAM.79109
dc.identifier.eissn2399-3642
dc.identifier.issn2399-3642
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331658
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.departmentDepartment of Public Health And Primary Care, Cancer Genetic Epidemiology
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleRare germline copy number variants (CNVs) and breast cancer risk
dc.typeArticle
dcterms.dateAccepted2021-12-01
prism.publicationNameCommunications Biology
pubs.funder-project-idCancer Research UK (CRUK-A16563)
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1038/s42003-021-02990-6

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