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

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 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 10(-3)). Chromosome conformation capture identifies interactions betw... Mehr ...

Verfasser: Lawrenson, Kate
Kar, Siddhartha
McCue, Karen
Kuchenbaeker, Karoline
Michailidou, Kyriaki
Tyrer, Jonathan
Beesley, Jonathan
Ramus, Susan J
Li, Qiyuan
Delgado, Melissa K
Lee, Janet M
Aittomäki, Kristiina
Andrulis, Irene L
Anton-Culver, Hoda
Arndt, Volker
Arun, Banu K
Arver, Brita
Bandera, Elisa V
Barile, Monica
Barkardottir, Rosa B
Barrowdale, Daniel
Beckmann, Matthias W
Benitez, Javier
Berchuck, Andrew
Bisogna, Maria
Bjorge, Line
Blomqvist, Carl
Blot, William
Bogdanova, Natalia
Bojesen, Anders
Bojesen, Stig E
Bolla, Manjeet K
Bonanni, Bernardo
Børresen-Dale, Anne-Lise
Brauch, Hiltrud
Brennan, Paul
Brenner, Hermann
Bruinsma, Fiona
Brunet, Joan
Buhari, Shaik Ahmad
Burwinkel, Barbara
Butzow, Ralf
Buys, Saundra S
Cai, Qiuyin
Caldes, Trinidad
Campbell, Ian
Canniotto, Rikki
Chang-Claude, Jenny
Chiquette, Jocelyne
Choi, Ji-Yeob
Claes, Kathleen BM
GEMO Study Collaborators
Cook, Linda S
Cox, Angela
Cramer, Daniel W
Cross, Simon S
Cybulski, Cezary
Czene, Kamila
Daly, Mary B
Damiola, Francesca
Dansonka-Mieszkowska, Agnieszka
Darabi, Hatef
Dennis, Joe
Devilee, Peter
Diez, Orland
Doherty, Jennifer A
Domchek, Susan M
Dorfling, Cecilia M
Dörk, Thilo
Dumont, Martine
Ehrencrona, Hans
Ejlertsen, Bent
Ellis, Steve",EMBRACE,"Engel, Christoph
Lee, Eunjung
Evans, D Gareth
Fasching, Peter A
Feliubadalo, Lidia
Figueroa, Jonine
Flesch-Janys, Dieter
Fletcher, Olivia
Flyger, Henrik
Foretova, Lenka
Fostira, Florentia
Foulkes, William D
Fridley, Brooke L
Friedman, Eitan
Frost, Debra
Gambino, Gaetana
Ganz, Patricia A
Garber, Judy
García-Closas, Montserrat
Gentry-Maharaj, Aleksandra
Ghoussaini, Maya
Giles, Graham G
Glasspool, Rosalind
Godwin, Andrew K
Goldberg, Mark S
Goldgar, David E
Dokumenttyp: Artikel
Erscheinungsdatum: 2016
Reihe/Periodikum: Nature communications, vol 7, iss 1
Verlag/Hrsg.: eScholarship
University of California
Schlagwörter: GEMO Study Collaborators / EMBRACE / Hereditary Breast and Ovarian Cancer Research Group Netherlands / KConFab Investigators / Australian Ovarian Cancer Study Group / Chromosomes / Human / Pair 19 / Humans / Breast Neoplasms / Ovarian Neoplasms / Genetic Predisposition to Disease / RNA / Messenger / Genotype / Polymorphism / Single Nucleotide / Alleles / African Continental Ancestry Group / Asian Continental Ancestry Group / Female / Genome-Wide Association Study / Prevention / Breast Cancer / Ovarian Cancer / Cancer / Rare Diseases / Genetics / 2.1 Biological and endogenous factors
Sprache: unknown
Permalink: https://search.fid-benelux.de/Record/base-28747660
Datenquelle: BASE; Originalkatalog
Powered By: BASE
Link(s) : https://escholarship.org/uc/item/78d894k9

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 × 10(-20)), ER-negative BC (P=1.1 × 10(-13)), BRCA1-associated BC (P=7.7 × 10(-16)) and triple negative BC (P-diff=2 × 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10(-3)) and ABHD8 (P<2 × 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.