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

Lawrenson, Kate ; Kar, Siddhartha ; McCue, Karen ; Kuchenbaeker, Karoline ; Michailidou, Kyriaki ; Tyrer, Jonathan ; Beesley, Jonathan ; Ramus, Susan J. ; Li, Qiyuan and Delgado, Melissa K. , et al. (2016) In Nature Communications 7.
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 × 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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
7
article number
12675
publisher
Nature Publishing Group
external identifiers
  • scopus:84987880304
  • wos:000385285100002
  • pmid:27601076
ISSN
2041-1723
DOI
10.1038/ncomms12675
language
English
LU publication?
yes
id
beb9d88a-99d9-48ff-915a-49012509606d
date added to LUP
2016-11-08 16:11:08
date last changed
2024-06-28 18:38:37
@article{beb9d88a-99d9-48ff-915a-49012509606d,
  abstract     = {{<p>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<sup>-20</sup>), ER-negative BC (P=1.1 × 10<sup>-13</sup>), BRCA1-associated BC (P=7.7 × 10<sup>-16</sup>) and triple negative BC (P-diff=2 × 10<sup>-5</sup>). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10<sup>-3</sup>) and ABHD8 (P&lt;2 × 10<sup>-3</sup>). 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.</p>}},
  author       = {{Lawrenson, Kate and Kar, Siddhartha and McCue, Karen and Kuchenbaeker, Karoline and Michailidou, Kyriaki and Tyrer, Jonathan and Beesley, Jonathan and Ramus, Susan J. and Li, Qiyuan and Delgado, Melissa K. and Lee, Janet M. and Aittomäki, Kristiina and Andrulis, Irene L. and Anton-Culver, Hoda and Arndt, Volker and Arun, Banu K. and Arver, Brita and Bandera, Elisa V. and Barile, Monica and Barkardottir, Rosa B. and Barrowdale, Daniel and Beckmann, Matthias W. and Benitez, Javier and Berchuck, Andrew and Bisogna, Maria and Bjorge, Line and Blomqvist, Carl and Blot, William and Bogdanova, Natalia and Bojesen, Anders and Bojesen, Stig E. and Bolla, Manjeet K. and Bonanni, Bernardo and Børresen-Dale, Anne Lise and Brauch, Hiltrud and Brennan, Paul and Brenner, Hermann and Bruinsma, Fiona and Brunet, Joan and Buhari, Shaik Ahmad and Burwinkel, Barbara and Butzow, Ralf and Buys, Saundra S. and Cai, Qiuyin and Caldes, Trinidad and Campbell, Ian and Canniotto, Rikki and Chang-Claude, Jenny and Chiquette, Jocelyne and Choi, Ji Yeob and Claes, Kathleen B M and Cook, Linda S. and Cox, Angela and Cramer, Daniel W. and Cross, Simon S. and Cybulski, Cezary and Czene, Kamila and Daly, Mary B. and Damiola, Francesca and Dansonka-Mieszkowska, Agnieszka and Darabi, Hatef and Dennis, Joe and Devilee, Peter and Diez, Orland and Doherty, Jennifer A. and Domchek, Susan M. and Dorfling, Cecilia M. and Dörk, Thilo and Dumont, Martine and Ehrencrona, Hans and Ejlertsen, Bent and Ellis, Steve and Engel, Christoph and Lee, Eunjung and Evans, D. 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Peter J. and Huzarski, Tomasz and Imyanitov, Evgeny N. and Isaacs, Claudine and Ito, Hidemi and Jakubowska, Anna and Janavicius, Ramunas and Jensen, Allan and John, Esther M. and Johnson, Nichola and Kabisch, Maria and Kang, Daehee and Kapuscinski, Miroslav and Karlan, Beth Y. and Khan, Sofia and Kiemeney, Lambertus A. and Kjaer, Susanne Kruger and Knight, Julia A. and Konstantopoulou, Irene and Kosma, Veli Matti and Kristensen, Vessela and Kupryjanczyk, Jolanta and Kwong, Ava and De La Hoya, Miguel and Laitman, Yael and Lambrechts, Diether and Le, Nhu and De Leeneer, Kim and Lester, Jenny and Levine, Douglas A. and Li, Jingmei and Lindblom, Annika and Long, Jirong and Lophatananon, Artitaya and Loud, Jennifer T. and Lu, Karen and Lubinski, Jan and Mannermaa, Arto and Manoukian, Siranoush and Le Marchand, Loic and Margolin, Sara and Marme, Frederik and Massuger, Leon F A G and Matsuo, Keitaro and Mazoyer, Sylvie and McGuffog, Lesley and McLean, Catriona and McNeish, Iain and Meindl, 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John and Porteous, Mary E. and Brady, Angela and Barwell, Julian and Foo, Claire and Lalloo, Fiona and Side, Lucy E. and Eason, Jacqueline and Henderson, Alex and Walker, Lisa and Cook, Jackie and Snape, Katie and Murray, Alex and McCann, Emma and Rookus, M. A. and Van Leeuwen, F. E. and Van Der Kolk, L. E. and Schmidt, M. K. and Russell, N. S. and De Lange, J. L. and Wijnands, R. and Collée, J. M. and Hooning, M. J. and Seynaeve, C. and Van Deurzen, C. H M and Obdeijn, I. M. and Van Asperen, C. J. and Tollenaar, R. A E M and Van Cronenburg, T. C T E F and Kets, C. M. and Ausems, M. G E M and Van Der Pol, C. C. and Van Os, T. A M and Waisfisz, Q. and Meijers-Heijboer, H. E J and Gómez-Garcia, E. B. and Oosterwijk, J. C. and Mourits, M. J. and De Bock, G. H. and Vasen, H. F. and Siesling, S. and Verloop, J. and Overbeek, L. I H and Fox, Stephen and Kirk, Judy and Lindeman, Geoff and Price, Melanie}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{09}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus}},
  url          = {{http://dx.doi.org/10.1038/ncomms12675}},
  doi          = {{10.1038/ncomms12675}},
  volume       = {{7}},
  year         = {{2016}},
}