Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

dc.contributor.authorLawrenson, Kate
dc.contributor.authorKar, Siddhartha
dc.contributor.authorMcCue, Karen
dc.contributor.authorKuchenbaeker, Karoline
dc.contributor.authorMichailidou, Kyriaki
dc.contributor.authorTyrer, Jonathan
dc.contributor.authorBeesley, Jonathan
dc.contributor.authorRamus, Susan J.
dc.contributor.authorLi, Qiyuan
dc.contributor.authorDelgado, Melissa K.
dc.contributor.authorLee, Janet M.
dc.contributor.authorAittomaki, Kristiina
dc.contributor.authorAndrulis, Irene L.
dc.contributor.authorAnton-Culver, Hoda
dc.contributor.authorArndt, Volker
dc.contributor.authorArun, Banu K.
dc.contributor.authorArver, Brita
dc.contributor.authorBandera, Elisa V.
dc.contributor.authorBarile, Monica
dc.contributor.authorBarkardottir, Rosa B.
dc.contributor.authorBarrowdale, Daniel
dc.contributor.authorBeckmann, Matthias W.
dc.contributor.authorBenitez, Javier
dc.contributor.authorBerchuck, Andrew
dc.contributor.authorBisogna, Maria
dc.contributor.authorBjorge, Line
dc.contributor.authorBlomqvist, Carl
dc.contributor.authorBlot, William
dc.contributor.authorBogdanova, Natalia
dc.contributor.authorBojesen, Anders
dc.contributor.authorBojesen, Stig E.
dc.contributor.authorBolla, Manjeet K.
dc.contributor.authorBonanni, Bernardo
dc.contributor.authorBorresen-Dale, Anne-Lise
dc.contributor.authorBrauch, Hiltrud
dc.contributor.authorBrennan, Paul
dc.contributor.authorBrenner, Hermann
dc.contributor.authorBruinsma, Fiona
dc.contributor.authorBrunet, Joan
dc.contributor.authorBuhari, Shaik Ahmad
dc.contributor.authorBurwinkel, Barbara
dc.contributor.authorButzow, Ralf
dc.contributor.authorBuys, Saundra S.
dc.contributor.authorCai, Qiuyin
dc.contributor.authorCaldes, Trinidad
dc.contributor.authorCanniotto, Rikki
dc.contributor.authorChang-Claude, Jenny
dc.contributor.authorChiquette, Jocelyne
dc.contributor.authorChoi, Ji-Yeob
dc.contributor.authorClaes, Kathleen B.M.
dc.contributor.authorGEMO Study Collaborators
dc.contributor.authorCampbell, Ian
dc.contributor.authorCook, Linda S.
dc.contributor.authorCox, Angela
dc.contributor.authorCramer, Daniel W.
dc.contributor.authorCross, Simon S.
dc.contributor.authorCybulski, Cezary
dc.contributor.authorCzene, Kamila
dc.contributor.authorDaly, Mary B.
dc.contributor.authorDamiola, Francesca
dc.contributor.authorDansonka-Mieszkowskaÿÿ, Agnieszka
dc.contributor.authorDarabi, Hatef
dc.contributor.authorDennis, Joe
dc.contributor.authorDevilee, Peter
dc.contributor.authorDiez, Orland
dc.contributor.authorDoherty, Jennifer A.
dc.contributor.authorDomchek, Susan M.
dc.contributor.authorDorfling, Cecilia Maria
dc.contributor.authorDork, Thilo
dc.contributor.authorDumont, Martine
dc.contributor.authorEhrencrona, Hans
dc.contributor.authorEjlertsen, Bent
dc.contributor.authorEllis, Steve
dc.contributor.authorEMBRACE
dc.contributor.authorEngel, Christoph
dc.contributor.authorLee, Eunjung
dc.contributor.authorEvans, D. Gareth
dc.contributor.authorFasching, Peter A.
dc.contributor.authorFeliubadalo, Lidia
dc.contributor.authorFigueroa, Jonine
dc.contributor.authorFlesch-Janys, Dieter
dc.contributor.authorFletcher, Olivia
dc.contributor.authorFlyger, Henrik
dc.contributor.authorForetova, Lenka
dc.contributor.authorFostira, Florentia
dc.contributor.authorFoulkes, William D.
dc.contributor.authorFridley, Brooke L.
dc.contributor.authorFriedman, Eitan
dc.contributor.authorFrost, Debra
dc.contributor.authorGambino, Gaetana
dc.contributor.authorGarber, Judy
dc.contributor.authorGarcıa-Closas, Montserrat
dc.contributor.authorGentry-Maharaj, Aleksandra
dc.contributor.authorGhoussaini, Maya
dc.contributor.authorGiles, Graham G.
dc.contributor.authorGlasspool, Rosalind
dc.contributor.authorGodwin, Andrew K.
dc.contributor.authorGoldberg, Mark S.
dc.contributor.authorGoldgar, David E.
dc.contributor.authorGonzalez-Neira, Anna
dc.contributor.authorGoode, Ellen L.
dc.contributor.authorGoodman, Marc T.
dc.contributor.authorGreene, Mark H.
dc.contributor.authorGronwald, Jacek
dc.contributor.authorGuenel, Pascal
dc.contributor.authorHaiman, Christopher A.
dc.contributor.authorHall, Per
dc.contributor.authorHallberg, Emily
dc.contributor.authorHamann, Ute
dc.contributor.authorHansen, Thomas V.O.
dc.contributor.authorHarrington, Patricia A.
dc.contributor.authorHartman, Mikael
dc.contributor.authorHassan, Norhashimah
dc.contributor.authorHealey, Sue
dc.contributor.authorThe Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)
dc.contributor.authorHeitz, Florian
dc.contributor.authorHerzog, Josef
dc.contributor.authorHogdall, Estrid
dc.contributor.authorHogdall, Claus K.
dc.contributor.authorHogervorst, Frans B.L.
dc.contributor.authorHollestelle, Antoinette
dc.contributor.authorHopper, John L.
dc.contributor.authorHulick, Peter J.
dc.contributor.authorHuzarski, Tomasz
dc.contributor.authorImyanitov, Evgeny N.
dc.contributor.authorKConFab Investigators
dc.contributor.authorAustralian Ovarian Cancer Study Group
dc.contributor.authorIsaacs, Claudine
dc.contributor.authorIto, Hidemi
dc.contributor.authorJakubowska, Anna
dc.contributor.authorJanavicius, Ramunas
dc.contributor.authorJensen, Allan
dc.contributor.authorJohn, Esther M.
dc.contributor.authorJohnson, Nichola
dc.contributor.authorKabisch, Maria
dc.contributor.authorKang, Daehee
dc.contributor.authorKapuscinski, Miroslav
dc.contributor.authorKarlan, Beth Y.
dc.contributor.authorKhan, Sofia
dc.contributor.authorKiemeney, Lambertus A.
dc.contributor.authorKjaer, Susanne Kruger
dc.contributor.authorKnight, Julia A.
dc.contributor.authorKonstantopoulou, Irene
dc.contributor.authorKosma, Veli-Matti
dc.contributor.authorKristensen, Vessela
dc.contributor.authorKupryjanczyk, Jolanta
dc.contributor.authorKwong, Ava
dc.contributor.authorDe la Hoya, Miguel
dc.contributor.authorLaitman, Yael
dc.contributor.authorLambrechts, Diether
dc.contributor.authorLe, Nhu
dc.contributor.authorDe Leeneer, Kim
dc.contributor.authorLester, Jenny
dc.contributor.authorLevine, Douglas A.
dc.contributor.authorLi, Jingmei
dc.contributor.authorLindblom, Annika
dc.contributor.authorLong, Jirong
dc.contributor.authorLophatananon, Artitaya
dc.contributor.authorLoud, Jennifer T.
dc.contributor.authorLu, Karen
dc.contributor.authorLubinski, Jan
dc.contributor.authorMannermaa, Arto
dc.contributor.authorManoukian, Siranoush
dc.contributor.authorLe Marchand, Loic
dc.contributor.authorMargolin, Sara
dc.contributor.authorMarme, Frederik
dc.contributor.authorMassuger, Leon F.A.G.
dc.contributor.authorMatsuo, Keitaro
dc.contributor.authorMazoyer, Sylvie
dc.contributor.authorMcGuffog, Lesley
dc.contributor.authorMcLean, Catriona
dc.contributor.authorMcNeish, Iain
dc.contributor.authorMeindl, Alfons
dc.contributor.authorMenon, Usha
dc.contributor.authorMensenkamp, Arjen R.
dc.contributor.authorMilne, Roger L.
dc.contributor.authorMontagna, Marco
dc.contributor.authorMoysich, Kirsten B.
dc.contributor.authorMuir, Kenneth
dc.contributor.authorMulligan, Anna Marie
dc.contributor.authorNathanson, Katherine L.
dc.contributor.authorNess, Roberta B.
dc.contributor.authorNeuhausen, Susan L.
dc.contributor.authorNevanlinna, Heli
dc.contributor.authorNord, Silje
dc.contributor.authorNussbaum, Robert L.
dc.contributor.authorOdunsi, Kunle
dc.contributor.authorOffit, Kenneth
dc.contributor.authorOlopade, Olufunmilayo I.
dc.contributor.authorOlson, Janet E.
dc.contributor.authorOlswold, Curtis
dc.contributor.authorO’Malley, David
dc.contributor.authorOrlow, Irene
dc.contributor.authorOrr, Nick
dc.contributor.authorOsorio, Ana
dc.contributor.authorPark, Sue Kyung
dc.contributor.authorPearce, Celeste L.
dc.contributor.authorPejovic, Tanja
dc.contributor.authorPeterlongo, Paolo
dc.contributor.authorPfeiler, Georg
dc.contributor.authorPhelan, Catherine M.
dc.contributor.authorPoole, Elizabeth M.
dc.contributor.authorPylkas, Katri
dc.contributor.authorRadice, Paolo
dc.contributor.authorRantala, Johanna
dc.contributor.authorRashid, Muhammad Usman
dc.contributor.authorRennert, Gad
dc.contributor.authorRhenius, Valerie
dc.contributor.authorRhiem, Kerstin
dc.contributor.authorRisch, Harvey A.
dc.contributor.authorRodriguez, Guz
dc.contributor.authorRossing, Mary Anne
dc.contributor.authorRudolph, Anja
dc.contributor.authorSalvesen, Helga B.
dc.contributor.authorSangrajrang, Suleeporn
dc.contributor.authorSawyer, Elinor J.
dc.contributor.authorSchildkraut, Joellen M.
dc.contributor.authorSchmidt, Marjanka K.
dc.contributor.authorSchmutzler, Rita K.
dc.contributor.authorSellers, Thomas A.
dc.contributor.authorSeynaeve, Caroline
dc.contributor.authorShah, Mitul
dc.contributor.authorShen, Chen-Yang
dc.contributor.authorShu, Xiao-Ou
dc.contributor.authorSieh, Weiva
dc.contributor.authorSinger, Christian F.
dc.contributor.authorSinilnikova, Olga M.
dc.contributor.authorSlager, Susan
dc.contributor.authorSong, Honglin
dc.contributor.authorSoucy, Penny
dc.contributor.authorSouthey, Melissa C.
dc.contributor.authorStenmark-Askmalm, Marie
dc.contributor.authorStoppa-Lyonnet, Dominique
dc.contributor.authorTeo, Soo H.
dc.contributor.authorTerry, Kathryn L.
dc.contributor.authorTerry, Mary Beth
dc.contributor.authorThomassen, Mads
dc.contributor.authorTibiletti, Maria Grazia
dc.contributor.authorTihomirova, Laima
dc.contributor.authorTognazzo, Silvia
dc.contributor.authorToland, Amanda Ewart
dc.contributor.authorTomlinson, Ian
dc.contributor.authorTorres, Diana
dc.contributor.authorTruong, Therese
dc.contributor.authorTseng, Chiu-chen
dc.contributor.authorTung, Nadine
dc.contributor.authorTworoger, Shelley S.
dc.contributor.authorVachon, Celine
dc.contributor.authorVan den Ouweland, Ans M.W.
dc.contributor.authorVan Doorn, Helena C.
dc.contributor.authorJansen van Rensburg, Elizabeth
dc.contributor.authorVan’t Veer, Laura J.
dc.contributor.authorVanderstichele, Adriaan
dc.contributor.authorVergote, Ignace
dc.contributor.authorVijai, Joseph
dc.contributor.authorWang, Qin
dc.contributor.authorWang-Gohrke, Shan
dc.contributor.authorWeitzel, Jeffrey N.
dc.contributor.authorWentzensen, Nicolas
dc.contributor.authorWhittemore, Alice S.
dc.contributor.authorWildiers, Hans
dc.contributor.authorWinqvist, Robert
dc.contributor.authorWu, Anna H.
dc.contributor.authorYannoukakos, Drakoulis
dc.contributor.authorYoon, Sook-Yee
dc.contributor.authorYu, Jyh-Cherng
dc.contributor.authorZheng, Wei
dc.contributor.authorZheng, Ying
dc.contributor.authorKhanna, Kum Kum
dc.contributor.authorSimard, Jacques
dc.contributor.authorMonteiro, Alvaro N.
dc.contributor.authorFrench, Juliet D.
dc.contributor.authorCouch, Fergus J.
dc.contributor.authorFreedman, Matthew L.
dc.contributor.authorEaston, Douglas F.
dc.contributor.authorDunning, Alison M.
dc.contributor.authorPharoah, Paul D.
dc.contributor.authorEdwards, Stacey L.
dc.contributor.authorChenevix-Trench, Georgia
dc.contributor.authorAntoniou, Antonis C.
dc.contributor.authorGayther, Simon A.
dc.date.accessioned2016-10-14T09:57:43Z
dc.date.available2016-10-14T09:57:43Z
dc.date.issued2016-09-07
dc.description.abstractA 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 (P¼9.2 10 20), ER-negative BC (P¼1.1 10 13), BRCA1-associated BC (P¼7.7 10 16) and triple negative BC (P-diff¼2 10 5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P¼2 10 3) and ABHD8 (Po2 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 30-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.en_ZA
dc.description.departmentGeneticsen_ZA
dc.description.librarianam2016en_ZA
dc.description.sponsorshipThe COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175—HEALTH-F2-2009- 223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). The CIMBA data management and analytical work is funded by Cancer Research UK (C12292/A11174, C12292/A20861). Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based on data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.en_ZA
dc.description.urihttp://www.nature.com/naturecommunicationsen_ZA
dc.identifier.citationLawrenson, K. et al. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature Communications. 7:12675 doi: 10.1038/ncomms12675 (2016).en_ZA
dc.identifier.issn2041-1723
dc.identifier.other10.1038/ncomms12675
dc.identifier.urihttp://hdl.handle.net/2263/57318
dc.language.isoenen_ZA
dc.publisherNature Publishing Groupen_ZA
dc.rights© The Author(s) 2016. This work is licensed under a Creative Commons Attribution 4.0 International License.en_ZA
dc.subjectLocusen_ZA
dc.subjectRisken_ZA
dc.subjectBreast cancer (BC)en_ZA
dc.subjectOvarian cancer (OC)en_ZA
dc.titleFunctional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locusen_ZA
dc.typeArticleen_ZA

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