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

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 BarkardottirDaniel 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, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, GEMO Study Collaborators

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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 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.

Original languageEnglish
Article number12675
Number of pages22
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 7 Sep 2016

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loci
breast
Ovarian Neoplasms
Single Nucleotide Polymorphism
cancer
Alleles
Breast Neoplasms
magnetic permeability
Assays
3' Untranslated Regions
Chromosomes
Luciferases
Gene expression
Triple Negative Breast Neoplasms
Conformations
Genes
RNA Stability
Messenger RNA
Transcriptional Activation
deletion

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Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., ... GEMO Study Collaborators (2016). Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature Communications, 7, [12675]. https://doi.org/10.1038/ncomms12675

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; 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; GEMO Study Collaborators.

In: Nature Communications, Vol. 7, 12675, 07.09.2016.

Research output: Contribution to journalArticle

Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, J-Y & GEMO Study Collaborators 2016, 'Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus', Nature Communications, vol. 7, 12675. https://doi.org/10.1038/ncomms12675
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 ; GEMO Study Collaborators. / Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. In: Nature Communications. 2016 ; Vol. 7.
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title = "Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus",
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 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.",
author = "Kate Lawrenson and Siddhartha Kar and Karen McCue and Karoline Kuchenbaeker and Kyriaki Michailidou and Jonathan Tyrer and Jonathan Beesley and Ramus, {Susan J} and Qiyuan Li and Delgado, {Melissa K} and Lee, {Janet M} and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Arun, {Banu K} and Brita Arver and Bandera, {Elisa V} and Monica Barile and Barkardottir, {Rosa B} and Daniel Barrowdale and Beckmann, {Matthias W} and Javier Benitez and Andrew Berchuck and Maria Bisogna and Line Bjorge and Carl Blomqvist and William Blot and Natalia Bogdanova and Anders Bojesen and Bojesen, {Stig E} and Bolla, {Manjeet K} and Bernardo Bonanni and Anne-Lise B{\o}rresen-Dale and Hiltrud Brauch and Paul Brennan and Hermann Brenner and Fiona Bruinsma and Joan Brunet and Buhari, {Shaik Ahmad} and Barbara Burwinkel and Ralf Butzow and Buys, {Saundra S} and Qiuyin Cai and Trinidad Caldes and Ian Campbell and Rikki Canniotto and Jenny Chang-Claude and Jocelyne Chiquette and Ji-Yeob Choi and {GEMO Study Collaborators}",
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T1 - Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

AU - Lawrenson, Kate

AU - Kar, Siddhartha

AU - McCue, Karen

AU - Kuchenbaeker, Karoline

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan

AU - Beesley, Jonathan

AU - Ramus, Susan J

AU - Li, Qiyuan

AU - Delgado, Melissa K

AU - Lee, Janet M

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Arun, Banu K

AU - Arver, Brita

AU - Bandera, Elisa V

AU - Barile, Monica

AU - Barkardottir, Rosa B

AU - Barrowdale, Daniel

AU - Beckmann, Matthias W

AU - Benitez, Javier

AU - Berchuck, Andrew

AU - Bisogna, Maria

AU - Bjorge, Line

AU - Blomqvist, Carl

AU - Blot, William

AU - Bogdanova, Natalia

AU - Bojesen, Anders

AU - Bojesen, Stig E

AU - Bolla, Manjeet K

AU - Bonanni, Bernardo

AU - Børresen-Dale, Anne-Lise

AU - Brauch, Hiltrud

AU - Brennan, Paul

AU - Brenner, Hermann

AU - Bruinsma, Fiona

AU - Brunet, Joan

AU - Buhari, Shaik Ahmad

AU - Burwinkel, Barbara

AU - Butzow, Ralf

AU - Buys, Saundra S

AU - Cai, Qiuyin

AU - Caldes, Trinidad

AU - Campbell, Ian

AU - Canniotto, Rikki

AU - Chang-Claude, Jenny

AU - Chiquette, Jocelyne

AU - Choi, Ji-Yeob

AU - GEMO Study Collaborators

N1 - We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out, in particular those involved in the COGS project: Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility.

PY - 2016/9/7

Y1 - 2016/9/7

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms12675

DO - 10.1038/ncomms12675

M3 - Article

C2 - 27601076

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 12675

ER -