Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

GEMO Study Collaborators; EMBRACE Collaborators; SWE-BRCA Investigators; KConFab Investigators; HEBON Investigators; Christopher Hakkaart; John F. Pearson; Louise Marquart; Joe Dennis; George A.R. Wiggins; Daniel R. Barnes; Bridget A. Robinson; Peter D. Mace; Kristiina Aittomäki; Irene L. Andrulis; Banu K. Arun; Jacopo Azzollini; Judith Balmaña; Rosa B. Barkardottir; Sami Belhadj; Lieke Berger; Marinus J. Blok; Susanne E. Boonen; Julika Borde; Angela R. Bradbury; Joan Brunet; Saundra S. Buys; Maria A. Caligo; Ian Campbell; Wendy K. Chung; Kathleen B.M. Claes; Marie Agnès Collonge-Rame; Jackie Cook; Casey Cosgrove; Fergus J. Couch; Mary B. Daly; Sita Dandiker; Rosemarie Davidson; Miguel de la Hoya; Robin de Putter; Capucine Delnatte; Mallika Dhawan; Orland Diez; Yuan Chun Ding; Susan M. Domchek; Alan Donaldson; Jacqueline Eason; Douglas F. Easton; Hans Ehrencrona; Christoph Engel; D. Gareth Evans; Ulrike Faust; Lidia Feliubadaló; Florentia Fostira; Eitan Friedman

doi:10.1038/s42003-022-03978-6

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, KConFab Investigators, HEBON Investigators, Christopher Hakkaart, John F. Pearson, Louise Marquart, Joe Dennis, George A.R. Wiggins, Daniel R. Barnes, Bridget A. Robinson, Peter D. Mace, Kristiina Aittomäki, Irene L. Andrulis, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Sami BelhadjLieke Berger, Marinus J. Blok, Susanne E. Boonen, Julika Borde, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Maria A. Caligo, Ian Campbell, Wendy K. Chung, Kathleen B.M. Claes, Marie Agnès Collonge-Rame, Jackie Cook, Casey Cosgrove, Fergus J. Couch, Mary B. Daly, Sita Dandiker, Rosemarie Davidson, Miguel de la Hoya, Robin de Putter, Capucine Delnatte, Mallika Dhawan, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Alan Donaldson, Jacqueline Eason, Douglas F. Easton, Hans Ehrencrona, Christoph Engel, D. Gareth Evans, Ulrike Faust, Lidia Feliubadaló, Florentia Fostira, Eitan Friedman

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Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Original language	English
Article number	1061
Pages (from-to)	1061
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03978-6
State	Published - Dec 2022

Keywords

BRCA1 Protein/genetics
BRCA2 Protein/genetics
Breast Neoplasms/genetics
DNA Copy Number Variations
Female
Genetic Predisposition to Disease
Heterozygote
Humans
RNA, Messenger

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s42003-022-03978-6

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GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, KConFab Investigators, HEBON Investigators, Hakkaart, C., Pearson, J. F., Marquart, L., Dennis, J., Wiggins, G. A. R., Barnes, D. R., Robinson, B. A., Mace, P. D., Aittomäki, K., Andrulis, I. L., Arun, B. K., Azzollini, J., Balmaña, J., Barkardottir, R. B., ... Friedman, E. (2022). Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Communications Biology, 5(1), 1061. Article 1061. https://doi.org/10.1038/s42003-022-03978-6

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title = "Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers",

abstract = "The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.",

keywords = "BRCA1 Protein/genetics, BRCA2 Protein/genetics, Breast Neoplasms/genetics, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Heterozygote, Humans, RNA, Messenger",

author = "{GEMO Study Collaborators} and {EMBRACE Collaborators} and {SWE-BRCA Investigators} and {KConFab Investigators} and {HEBON Investigators} and Christopher Hakkaart and Pearson, {John F.} and Louise Marquart and Joe Dennis and Wiggins, {George A.R.} and Barnes, {Daniel R.} and Robinson, {Bridget A.} and Mace, {Peter D.} and Kristiina Aittom{\"a}ki and Andrulis, {Irene L.} and Arun, {Banu K.} and Jacopo Azzollini and Judith Balma{\~n}a and Barkardottir, {Rosa B.} and Sami Belhadj and Lieke Berger and Blok, {Marinus J.} and Boonen, {Susanne E.} and Julika Borde and Bradbury, {Angela R.} and Joan Brunet and Buys, {Saundra S.} and Caligo, {Maria A.} and Ian Campbell and Chung, {Wendy K.} and Claes, {Kathleen B.M.} and Collonge-Rame, {Marie Agn{\`e}s} and Jackie Cook and Casey Cosgrove and Couch, {Fergus J.} and Daly, {Mary B.} and Sita Dandiker and Rosemarie Davidson and {de la Hoya}, Miguel and {de Putter}, Robin and Capucine Delnatte and Mallika Dhawan and Orland Diez and Ding, {Yuan Chun} and Domchek, {Susan M.} and Alan Donaldson and Jacqueline Eason and Easton, {Douglas F.} and Hans Ehrencrona and Christoph Engel and Evans, {D. Gareth} and Ulrike Faust and Lidia Feliubadal{\'o} and Florentia Fostira and Eitan Friedman",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-03978-6",

language = "English",

volume = "5",

pages = "1061",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Springer Nature",

number = "1",

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GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, KConFab Investigators, HEBON Investigators, Hakkaart, C, Pearson, JF, Marquart, L, Dennis, J, Wiggins, GAR, Barnes, DR, Robinson, BA, Mace, PD, Aittomäki, K, Andrulis, IL, Arun, BK, Azzollini, J, Balmaña, J, Barkardottir, RB, Belhadj, S, Berger, L, Blok, MJ, Boonen, SE, Borde, J, Bradbury, AR, Brunet, J, Buys, SS, Caligo, MA, Campbell, I, Chung, WK, Claes, KBM, Collonge-Rame, MA, Cook, J, Cosgrove, C, Couch, FJ, Daly, MB, Dandiker, S, Davidson, R, de la Hoya, M, de Putter, R, Delnatte, C, Dhawan, M, Diez, O, Ding, YC, Domchek, SM, Donaldson, A, Eason, J, Easton, DF, Ehrencrona, H, Engel, C, Evans, DG, Faust, U, Feliubadaló, L, Fostira, F & Friedman, E 2022, 'Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers', Communications Biology, vol. 5, no. 1, 1061, pp. 1061. https://doi.org/10.1038/s42003-022-03978-6

TY - JOUR

T1 - Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - SWE-BRCA Investigators

AU - KConFab Investigators

AU - HEBON Investigators

AU - Hakkaart, Christopher

AU - Pearson, John F.

AU - Marquart, Louise

AU - Dennis, Joe

AU - Wiggins, George A.R.

AU - Barnes, Daniel R.

AU - Robinson, Bridget A.

AU - Mace, Peter D.

AU - Aittomäki, Kristiina

AU - Andrulis, Irene L.

AU - Arun, Banu K.

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barkardottir, Rosa B.

AU - Belhadj, Sami

AU - Berger, Lieke

AU - Blok, Marinus J.

AU - Boonen, Susanne E.

AU - Borde, Julika

AU - Bradbury, Angela R.

AU - Brunet, Joan

AU - Buys, Saundra S.

AU - Caligo, Maria A.

AU - Campbell, Ian

AU - Chung, Wendy K.

AU - Claes, Kathleen B.M.

AU - Collonge-Rame, Marie Agnès

AU - Cook, Jackie

AU - Cosgrove, Casey

AU - Couch, Fergus J.

AU - Daly, Mary B.

AU - Dandiker, Sita

AU - Davidson, Rosemarie

AU - de la Hoya, Miguel

AU - de Putter, Robin

AU - Delnatte, Capucine

AU - Dhawan, Mallika

AU - Diez, Orland

AU - Ding, Yuan Chun

AU - Domchek, Susan M.

AU - Donaldson, Alan

AU - Eason, Jacqueline

AU - Easton, Douglas F.

AU - Ehrencrona, Hans

AU - Engel, Christoph

AU - Evans, D. Gareth

AU - Faust, Ulrike

AU - Feliubadaló, Lidia

AU - Fostira, Florentia

AU - Friedman, Eitan

PY - 2022/12

Y1 - 2022/12

N2 - The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

AB - The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/genetics

KW - DNA Copy Number Variations

KW - Female

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - RNA, Messenger

UR - http://www.scopus.com/inward/record.url?scp=85139349547&partnerID=8YFLogxK

U2 - 10.1038/s42003-022-03978-6

DO - 10.1038/s42003-022-03978-6

M3 - Article

C2 - 36203093

AN - SCOPUS:85139349547

SN - 2399-3642

VL - 5

SP - 1061

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 1061

ER -

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Abstract

Keywords

UN SDGs

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