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

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  • Kate Lawrenson
  • Siddhartha Kar
  • Karen McCue
  • Karoline Kuchenbaeker
  • Kyriaki Michailidou
  • Jonathan Tyrer
  • Jonathan Beesley
  • Susan J Ramus
  • Qiyuan Li
  • Melissa K Delgado
  • Janet M Lee
  • Kristiina Aittomäki
  • Irene L Andrulis
  • Hoda Anton-Culver
  • Volker Arndt
  • Banu K Arun
  • Brita Arver
  • Elisa V Bandera
  • Monica Barile
  • Rosa B Barkardottir
  • Daniel Barrowdale
  • Matthias W Beckmann
  • Javier Benitez
  • Andrew Berchuck
  • Maria Bisogna
  • Line Bjorge
  • Carl Blomqvist
  • William Blot
  • Natalia Bogdanova
  • Anders Bojesen
  • Stig E Bojesen
  • Manjeet K Bolla
  • Bernardo Bonanni
  • Anne-Lise Børresen-Dale
  • Hiltrud Brauch
  • Paul Brennan
  • Hermann Brenner
  • Fiona Bruinsma
  • Joan Brunet
  • Shaik Ahmad Buhari
  • Barbara Burwinkel
  • Ralf Butzow
  • Saundra S Buys
  • Qiuyin Cai
  • Bent Ejlertsen
  • Henrik Flyger
  • Thomas V O Hansen
  • Estrid Vilma Solyom Høgdall
  • Claus K Høgdall
  • Susanne Kruger Kjaer
  • GEMO Study Collaborators
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftNature Communications
Vol/bind7
Sider (fra-til)12675
ISSN2041-1723
DOI
StatusUdgivet - 7 sep. 2016

ID: 49468357