A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Juliette Coignard; Michael Lush; Jonathan Beesley; Tracy A O'Mara; Joe Dennis; Jonathan P Tyrer; Daniel R Barnes; Lesley McGuffog; Goska Leslie; Manjeet K Bolla; Muriel A Adank; Simona Agata; Thomas Ahearn; Kristiina Aittomäki; Irene L Andrulis; Hoda Anton-Culver; Volker Arndt; Norbert Arnold; Kristan J Aronson; Banu K Arun; Annelie Augustinsson; Jacopo Azzollini; Daniel Barrowdale; Caroline Baynes; Heiko Becher; Marina Bermisheva; Leslie Bernstein; Katarzyna Białkowska; Carl Blomqvist; Stig E Bojesen; Bernardo Bonanni; Ake Borg; Hiltrud Brauch; Hermann Brenner; Barbara Burwinkel; Saundra S Buys; Trinidad Caldés; Maria A Caligo; Daniele Campa; Brian D Carter; Jose E Castelao; Jenny Chang-Claude; Stephen J Chanock; Wendy K Chung; Kathleen B M Claes; Christine L Clarke; J Margriet Collée; Don M Conroy; Kamila Czene; Mary B Daly; GEMO Study Collaborators; EMBRACE Collaborators; HEBON Investigators; Encarna Gomez Garcia; KConFab Investigators; Nadine Andrieu

doi:10.1038/s41467-020-20496-3

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A O'Mara, Joe Dennis, Jonathan P Tyrer, Daniel R Barnes, Lesley McGuffog, Goska Leslie, Manjeet K Bolla, Muriel A Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J Aronson, Banu K ArunAnnelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heiko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Daniele Campa, Brian D Carter, Jose E Castelao, Jenny Chang-Claude, Stephen J Chanock, Wendy K Chung, Kathleen B M Claes, Christine L Clarke, J Margriet Collée, Don M Conroy, Kamila Czene, Mary B Daly, GEMO Study Collaborators, EMBRACE Collaborators, HEBON Investigators, Encarna Gomez Garcia, KConFab Investigators, Nadine Andrieu^*

^*Corresponding author for this work

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

Abstract

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

Original language	English
Article number	1078
Number of pages	22
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20496-3
Publication status	Published - 17 Feb 2021

Keywords

Adult
Alleles
BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
Female
Genetic Predisposition to Disease/genetics
Genome-Wide Association Study/methods
Genotype
Humans
Linkage Disequilibrium
Middle Aged
Mutation
Polymorphism, Single Nucleotide
Quantitative Trait Loci/genetics
Risk Factors

Access to Document

10.1038/s41467-020-20496-3Licence: CC BY

Cite this

Coignard, J., Lush, M., Beesley, J., O'Mara, T. A., Dennis, J., Tyrer, J. P., Barnes, D. R., McGuffog, L., Leslie, G., Bolla, M. K., Adank, M. A., Agata, S., Ahearn, T., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., Arndt, V., Arnold, N., Aronson, K. J., ... Andrieu, N. (2021). A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers. Nature Communications, 12(1), Article 1078. https://doi.org/10.1038/s41467-020-20496-3

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title = "A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers",

abstract = "Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.",

keywords = "Adult, Alleles, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, Female, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci/genetics, Risk Factors",

author = "Juliette Coignard and Michael Lush and Jonathan Beesley and O'Mara, {Tracy A} and Joe Dennis and Tyrer, {Jonathan P} and Barnes, {Daniel R} and Lesley McGuffog and Goska Leslie and Bolla, {Manjeet K} and Adank, {Muriel A} and Simona Agata and Thomas Ahearn and Kristiina Aittom{\"a}ki and Andrulis, {Irene L} and Hoda Anton-Culver and Volker Arndt and Norbert Arnold and Aronson, {Kristan J} and Arun, {Banu K} and Annelie Augustinsson and Jacopo Azzollini and Daniel Barrowdale and Caroline Baynes and Heiko Becher and Marina Bermisheva and Leslie Bernstein and Katarzyna Bia{\l}kowska and Carl Blomqvist and Bojesen, {Stig E} and Bernardo Bonanni and Ake Borg and Hiltrud Brauch and Hermann Brenner and Barbara Burwinkel and Buys, {Saundra S} and Trinidad Cald{\'e}s and Caligo, {Maria A} and Daniele Campa and Carter, {Brian D} and Castelao, {Jose E} and Jenny Chang-Claude and Chanock, {Stephen J} and Chung, {Wendy K} and Claes, {Kathleen B M} and Clarke, {Christine L} and Coll{\'e}e, {J Margriet} and Conroy, {Don M} and Kamila Czene and Daly, {Mary B} and {GEMO Study Collaborators} and {EMBRACE Collaborators} and {HEBON Investigators} and {Gomez Garcia}, Encarna and {KConFab Investigators} and Nadine Andrieu",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-020-20496-3",

language = "English",

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Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collée, JM, Conroy, DM, Czene, K, Daly, MB, GEMO Study Collaborators, EMBRACE Collaborators, HEBON Investigators, Gomez Garcia, E, KConFab Investigators & Andrieu, N 2021, 'A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers', Nature Communications, vol. 12, no. 1, 1078. https://doi.org/10.1038/s41467-020-20496-3

TY - JOUR

T1 - A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

AU - Coignard, Juliette

AU - Lush, Michael

AU - Beesley, Jonathan

AU - O'Mara, Tracy A

AU - Dennis, Joe

AU - Tyrer, Jonathan P

AU - Barnes, Daniel R

AU - McGuffog, Lesley

AU - Leslie, Goska

AU - Bolla, Manjeet K

AU - Adank, Muriel A

AU - Agata, Simona

AU - Ahearn, Thomas

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Arnold, Norbert

AU - Aronson, Kristan J

AU - Arun, Banu K

AU - Augustinsson, Annelie

AU - Azzollini, Jacopo

AU - Barrowdale, Daniel

AU - Baynes, Caroline

AU - Becher, Heiko

AU - Bermisheva, Marina

AU - Bernstein, Leslie

AU - Białkowska, Katarzyna

AU - Blomqvist, Carl

AU - Bojesen, Stig E

AU - Bonanni, Bernardo

AU - Borg, Ake

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Burwinkel, Barbara

AU - Buys, Saundra S

AU - Caldés, Trinidad

AU - Caligo, Maria A

AU - Campa, Daniele

AU - Carter, Brian D

AU - Castelao, Jose E

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Chung, Wendy K

AU - Claes, Kathleen B M

AU - Clarke, Christine L

AU - Collée, J Margriet

AU - Conroy, Don M

AU - Czene, Kamila

AU - Daly, Mary B

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - HEBON Investigators

AU - Gomez Garcia, Encarna

AU - KConFab Investigators

AU - Andrieu, Nadine

PY - 2021/2/17

Y1 - 2021/2/17

N2 - Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

AB - Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

KW - Adult

KW - Alleles

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome-Wide Association Study/methods

KW - Genotype

KW - Humans

KW - Linkage Disequilibrium

KW - Middle Aged

KW - Mutation

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci/genetics

KW - Risk Factors

U2 - 10.1038/s41467-020-20496-3

DO - 10.1038/s41467-020-20496-3

M3 - Article

C2 - 33597508

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1078

ER -