Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

dc.contributor.authorPainter, Jodie N.
dc.contributor.authorO'Mara, Tracy A.
dc.contributor.authorBatra, Jyotsna
dc.contributor.authorCheng, Timothy
dc.contributor.authorLose, Felicity A.
dc.contributor.authorDennis, Joe
dc.contributor.authorMichailidou, Kyriaki
dc.contributor.authorTyrer, Jonathan P.
dc.contributor.authorAhmed, Shahana
dc.contributor.authorFerguson, Kaltin
dc.contributor.authorHealey, Catherine S.
dc.contributor.authorKaufmann, Susanne
dc.contributor.authorHillman, Kristine M.
dc.contributor.authorWalpole, Carina
dc.contributor.authorMoya, Leire
dc.contributor.authorPollock, Pamela
dc.contributor.authorJones, Angela
dc.contributor.authorHowarth, Kimberley
dc.contributor.authorMartin, Lynn
dc.contributor.authorGorman, Maggie
dc.contributor.authorHodgson, Shirley
dc.contributor.authorDe Polanco, Ma. Magdalena Echeverry
dc.contributor.authorSans, Monica
dc.contributor.authorCarracedo, Angel
dc.contributor.authorCastellvi-Bel, Sergi
dc.contributor.authorRojas-Martinez, Augusto
dc.contributor.authorSantos, Erika
dc.contributor.authorTeixeira, Manuel R.
dc.contributor.authorCarvajal-Carmona, Luis
dc.contributor.authorShu, Xiao-Ou
dc.contributor.authorLong, Jirong
dc.contributor.authorZheng, Wei
dc.contributor.authorXiang, Yong-Bing
dc.contributor.authorMontgomery, Grant W.
dc.contributor.authorWebb, Penelope M.
dc.contributor.authorScott, Rodney J.
dc.contributor.authorMcEvoy, Mark
dc.contributor.authorAttia, John
dc.contributor.authorHolliday, Elizabeth
dc.contributor.authorMartin, Nicholas G.
dc.contributor.authorNyholt, Dale R.
dc.contributor.authorHenders, Anjali K.
dc.contributor.authorFasching, Peter A.
dc.contributor.authorHein, Alexander
dc.contributor.authorBeckmann, Matthias W.
dc.contributor.authorRenner, Stefan P.
dc.contributor.authorDörk, Thilo
dc.contributor.authorHillemanns, Peter
dc.contributor.authorDürst, Matthias
dc.contributor.authorRunnebaum, Ingo
dc.contributor.authorLambrechts, Diether
dc.contributor.authorCoenegrachts, Lieve
dc.contributor.authorSchrauwen, Stefanie
dc.contributor.authorAmant, Frederic
dc.contributor.authorWinterhoff, Boris
dc.contributor.authorDowdy, Sean C.
dc.contributor.authorGoode, Ellen L.
dc.contributor.authorTeoman, Attila
dc.contributor.authorSalvesen, Helga B.
dc.contributor.authorTrovik, Jone
dc.contributor.authorNjolstad, Tormund S.
dc.contributor.authorWerner, Henrica M.J.
dc.contributor.authorAshton, Katie
dc.contributor.authorProietto, Tony
dc.contributor.authorOtton, Geoffrey
dc.contributor.authorTzortzatos, Gerasimos
dc.contributor.authorMints, Miriam
dc.contributor.authorTham, Emma
dc.contributor.authorHall, Per
dc.contributor.authorCzene, Kamila
dc.contributor.authorLiu, Jianjun
dc.contributor.authorLi, Jingmei
dc.contributor.authorHopper, John L.
dc.contributor.authorSouthey, Melissa C.
dc.contributor.authorEkici, Arif B.
dc.contributor.authorRuebner, Matthias
dc.contributor.authorJohnson, Nicola
dc.contributor.authorPeto, Julian
dc.contributor.authorBurwinkel, Barbara
dc.contributor.authorMarme, Frederik
dc.contributor.authorBrenner, Hermann
dc.contributor.authorDieffenbach, Aida K.
dc.contributor.authorMeindl, Alfons
dc.contributor.authorBrauch, Hiltrud
dc.contributor.authorLindblom, Annika
dc.contributor.authorDepreeuw, Jeroen
dc.contributor.authorMoisse, Matthieu
dc.contributor.authorChang-Claude, Jenny
dc.contributor.authorRudolph, Anja
dc.contributor.authorCouch, Fergus J.
dc.contributor.authorOlson, Janet E.
dc.contributor.authorGiles, Graham G.
dc.contributor.authorBruinsma, Fiona
dc.contributor.authorCunningham, Julie M.
dc.contributor.authorFridley, Brooke L.
dc.contributor.authorBørresen-Dale, Anne-Lise
dc.contributor.authorKristensen, Vessela N.
dc.contributor.authorCox, Angela
dc.contributor.authorSwerdlow, Anthony J.
dc.contributor.authorOrr, Nicholas
dc.contributor.authorBolla, Manjeet K.
dc.contributor.authorWang, Qin
dc.contributor.authorWeber, Rachel Palmieri
dc.contributor.authorChen, Zhihua
dc.contributor.authorShah, Mitul
dc.contributor.authorFrench, Juliet D.
dc.contributor.authorPharoah, Paul D.P.
dc.contributor.authorDunning, Alison M.
dc.contributor.authorTomlinson, Ian
dc.contributor.authorEaston, Douglas F.
dc.contributor.authorEdwards, Stacey L.
dc.contributor.authorThompson, Deborah J.
dc.contributor.authorSpurdle, Amanda B.
dc.date.accessioned2016-09-08
dc.date.available2016-09-06
dc.date.created2015
dc.date.issued2016-09-08
dc.description.abstractCommon variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.en
dc.format.extent1478 - 1792
dc.identifier.citationHuman Molecular Genetics 24.5 (2015): S. 1478-1792. <http://hmg.oxfordjournals.org/content/24/5/1478.abstract>
dc.identifier.doihttps://doi.org/10.1093/hmg/ddu552
dc.identifier.opus-id7483
dc.identifier.urihttps://open.fau.de/handle/openfau/7483
dc.identifier.urnurn:nbn:de:bvb:29-opus4-74835
dc.language.isoen
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/de/deed.de
dc.subject.ddcDDC Classification::6 Technik, Medizin, angewandte Wissenschaften :: 61 Medizin und Gesundheit :: 610 Medizin und Gesundheit
dc.titleFine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risken
dc.typearticle
dcterms.publisherFriedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
local.journal.issue5
local.journal.titleHuman Molecular Genetics
local.journal.volume24
local.sendToDnbfree*
local.subject.fakultaetMedizinische Fakultät
local.subject.gnd-
local.subject.sammlungUniversität Erlangen-Nürnberg / Allianzlizenzen: Alle Beiträge sind mit Zustimmung der Rechteinhaber aufgrund einer DFG-geförderten Allianzlizenz frei zugänglich. / Allianzlizenzen 2015
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