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

GEMO Study Collaborators; 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; Trinidad Caldes; Ian Campbell; Rikki Cannioto; Jenny Chang-Claude; Antonis C. Antoniou; Simon A. Gayther

doi:10.1038/ncomms12675

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

GEMO Study Collaborators
, 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, Trinidad Caldes, Ian Campbell, Rikki Cannioto, Jenny Chang-Claude, Antonis C. Antoniou^*, Simon A. Gayther

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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 language	English
Article number	12675
Number of pages	22
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12675
Publication status	Published - 7-Sept-2016

Keywords

Alleles
Asian People/genetics
Black People/genetics
Breast Neoplasms/genetics
Chromosomes, Human, Pair 19/genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Ovarian Neoplasms/genetics
Polymorphism, Single Nucleotide
RNA, Messenger/genetics

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Author Correction: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
GEMO Study Collaborators, 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., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Bandera, E. V. & Barile, M. & 29 others, 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., Børresen-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., Cannioto, R. & Chang-Claude, J., 8-Sept-2025, In: Nature Communications. 16, p. 8237
Research output: Contribution to journal › Erratum

Cite this

GEMO Study Collaborators, 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., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arun, B. K., Arver, B., Bandera, E. V., ... Gayther, S. A. (2016). Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nature Communications, 7, Article 12675. https://doi.org/10.1038/ncomms12675

@article{902266a86c0b4e6a9bcc7d7ee4cb866d,

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.",

keywords = "Alleles, Asian People/genetics, Black People/genetics, Breast Neoplasms/genetics, Chromosomes, Human, Pair 19/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Ovarian Neoplasms/genetics, Polymorphism, Single Nucleotide, RNA, Messenger/genetics",

author = "\{GEMO Study Collaborators\} and 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 Cannioto and Jenny Chang-Claude and Antoniou, \{Antonis C.\} and Gayther, \{Simon A.\} and Oosterwijk, \{Jan C\} and Mourits, \{Marian J.E.\} and \{de Bock\}, \{G H\}",

year = "2016",

month = sep,

day = "7",

doi = "10.1038/ncomms12675",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

GEMO Study Collaborators, 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, Cannioto, R, Chang-Claude, J, Antoniou, AC & Gayther, SA 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

TY - JOUR

T1 - Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

AU - GEMO Study Collaborators

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 - Cannioto, Rikki

AU - Chang-Claude, Jenny

AU - Antoniou, Antonis C.

AU - Gayther, Simon A.

AU - Oosterwijk, Jan C

AU - Mourits, Marian J.E.

AU - de Bock, G H

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.

KW - Alleles

KW - Asian People/genetics

KW - Black People/genetics

KW - Breast Neoplasms/genetics

KW - Chromosomes, Human, Pair 19/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Ovarian Neoplasms/genetics

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger/genetics

U2 - 10.1038/ncomms12675

DO - 10.1038/ncomms12675

M3 - Article

C2 - 27601076

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12675

ER -

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

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Keywords

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

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