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Title: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
Author(s): Lawrenson, K.; Kar, S.; McCue, K.; Kuchenbaeker, K.; Michailidou, K.; Tyrer, J.; Beesley, J.; Ramus, S.J.; Li, Q.; Delgado, M.K.; Lee, J.M.; Aittomaki, K.; Andrulis, I.L.; Anton-Culver, H.; Arndt, V.; Arun, B.K.; Arver, B.; Bandera, E.V.; Barile, M.; Barkardottir, R.B.; Barrowdale, D.; Beckmann, M.W.; Benitez, J.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Blomqvist, C.; Blot, W.; Bogdanova, N.; Bojesen, A.; Bojesen, S.E.; Bolla, M.K.; Bonanni, B.; Borresen-Dale, A.L.; Brauch, H.; Brennan, P.; Brenner, H.; Bruinsma, F.; Brunet, J.; Buhari, S.A.; Burwinkel, B.; Butzow, R.; Buys, S.S.; Cai, Q.; Caldes, T.; Campbell, I.; Canniotto, R.; Chang-Claude, J.; Chiquette, J.; Choi, J.Y. ; Claes, K.B.; Cook, L.S.; Cox, A; Cramer, D.W; Cross, S.S.; Cybulski, C.; Czene, K.; Daly, M.B.; Damiola, F.; Dansonka-Mieszkowska, A.; Darabi, H.; Dennis, J.; Devilee, P.; Diez, O.; Doherty, J.A.; Domchek, S.M.; Dorfling, C.M.; Dork, T.; Dumont, M.; Ehrencrona, H.; Ejlertsen, B.; Ellis, S.; Engel, C.; Lee, E.; Evans, D.G.; Fasching, P.A.; Feliubadalo, L.; Figueroa, J.; Flesch-Janys, D.; Fletcher, O.; Flyger, H.; Foretova, L.; Fostira, F.; Foulkes, W.D.; Fridley, B.L.; Friedman, E.; Frost, D.; Gambino, G.; Ganz, P.A.; Garber, J.; Garcia-Closas, M.; Gentry-Maharaj, A.; Ghoussaini, M.; Giles, G.G.; Glasspool, R.; Godwin, A.K.; Goldberg, M.S.; Goldgar, D.E.; Gonzalez-Neira, A.; Goode, E.L.; Kiemeney, B. ; Massuger, L.F.A.G. ; Mensenkamp, A.R. ; et al.
Publication year: 2016
Source: Nature Communications, vol. 7, (2016), pp. 12675
ISSN: 2041-1723
DOI: https://doi.org/10.1038/ncomms12675
Publication type: Article / Letter to editor

Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/172592   https://hdl.handle.net/2066/172592

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Subject: Radboudumc 14: Tumours of the digestive tract RIMLS: Radboud Institute for Molecular Life Sciences
Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences
Radboudumc 17: Women's cancers RIMLS: Radboud Institute for Molecular Life Sciences
Organization: Urology
Health Evidence
Gynaecology
Human Genetics
Journal title:
Nature Communications
Volume: vol. 7
Page start: p. 12675
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 x 10(-20)), ER-negative BC (P=1.1 x 10(-13)), BRCA1-associated BC (P=7.7 x 10(-16)) and triple negative BC (P-diff=2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 x 10(-3)) and ABHD8 (P<2 x 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.

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