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

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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. / Hakkaart, Christopher; Pearson, John F.; Marquart, Louise; Dennis, Joe; Wiggins, George A. R.; Barnes, Daniel R.; Robinson, Bridget A.; Mace, Peter D.; Aittomäki, Kristiina; Andrulis, Irene L.; Arun, Banu K.; Azzollini, Jacopo; Balmaña, Judith; Barkardottir, Rosa B.; Belhadj, Sami; Berger, Lieke; Blok, Marinus J.; Boonen, Susanne E.; Borde, Julika; Bradbury, Angela R.; Brunet, Joan; Buys, Saundra S; Caligo, Maria A.; Campbell, Ian; Chung, Wendy K.; Claes, Kathleen B. M.; Collonge-Rame, Marie-Agnès; Cook, Jackie; Cosgrove, Casey; Couch, Fergus J.; Daly, Mary B.; Dandiker, Sita; Davidson, Rosemarie; de la Hoya, Miguel; de Putter, Robin; Delnatte, Capucine; Dhawan, Mallika; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M.; Donaldson, Alan; Eason, Jacqueline; Easton, Douglas F.; Ehrencrona, Hans; Engel, Christoph; Evans, D. Gareth; Faust, Ulrike; Feliubadaló, Lidia; Fostira, Florentia; Hansen, Thomas V. O.; Rossing, Caroline Maria; GEMO Study Collaborators; EMBRACE Collaborators; SWE-BRCA Investigators; kConFab Investigators; HEBON Investigators.

In: Communications Biology , Vol. 5, 1061, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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, M-A, 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, Hansen, TVO, Rossing, CM, GEMO Study Collaborators, EMBRACE Collaborators, SWE-BRCA Investigators, kConFab Investigators & HEBON Investigators 2022, 'Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers', Communications Biology , vol. 5, 1061. https://doi.org/10.1038/s42003-022-03978-6

APA

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., Belhadj, S., Berger, L., Blok, M. J., Boonen, S. E., Borde, J., ... HEBON Investigators (2022). Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Communications Biology , 5, [1061]. https://doi.org/10.1038/s42003-022-03978-6

Vancouver

Hakkaart C, Pearson JF, Marquart L, Dennis J, Wiggins GAR, Barnes DR et al. Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Communications Biology . 2022;5. 1061. https://doi.org/10.1038/s42003-022-03978-6

Author

Hakkaart, Christopher ; Pearson, John F. ; Marquart, Louise ; Dennis, Joe ; Wiggins, George A. R. ; Barnes, Daniel R. ; Robinson, Bridget A. ; Mace, Peter D. ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Arun, Banu K. ; Azzollini, Jacopo ; Balmaña, Judith ; Barkardottir, Rosa B. ; Belhadj, Sami ; Berger, Lieke ; Blok, Marinus J. ; Boonen, Susanne E. ; Borde, Julika ; Bradbury, Angela R. ; Brunet, Joan ; Buys, Saundra S ; Caligo, Maria A. ; Campbell, Ian ; Chung, Wendy K. ; Claes, Kathleen B. M. ; Collonge-Rame, Marie-Agnès ; Cook, Jackie ; Cosgrove, Casey ; Couch, Fergus J. ; Daly, Mary B. ; Dandiker, Sita ; Davidson, Rosemarie ; de la Hoya, Miguel ; de Putter, Robin ; Delnatte, Capucine ; Dhawan, Mallika ; Diez, Orland ; Ding, Yuan Chun ; Domchek, Susan M. ; Donaldson, Alan ; Eason, Jacqueline ; Easton, Douglas F. ; Ehrencrona, Hans ; Engel, Christoph ; Evans, D. Gareth ; Faust, Ulrike ; Feliubadaló, Lidia ; Fostira, Florentia ; Hansen, Thomas V. O. ; Rossing, Caroline Maria ; GEMO Study Collaborators ; EMBRACE Collaborators ; SWE-BRCA Investigators ; kConFab Investigators ; HEBON Investigators. / Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. In: Communications Biology . 2022 ; Vol. 5.

Bibtex

@article{49873e6ee14343e6b18aa71d8dee9132,
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.",
author = "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 Marie-Agn{\`e}s Collonge-Rame 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 Hansen, {Thomas V. O.} and Rossing, {Caroline Maria} and {GEMO Study Collaborators} and {EMBRACE Collaborators} and {SWE-BRCA Investigators} and {kConFab Investigators} and {HEBON Investigators}",
note = "Publisher Copyright: {\textcopyright} 2022. The Author(s).",
year = "2022",
doi = "10.1038/s42003-022-03978-6",
language = "English",
volume = "5",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "nature publishing group",

}

RIS

TY - JOUR

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

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 - Hansen, Thomas V. O.

AU - Rossing, Caroline Maria

AU - GEMO Study Collaborators

AU - EMBRACE Collaborators

AU - SWE-BRCA Investigators

AU - kConFab Investigators

AU - HEBON Investigators

N1 - Publisher Copyright: © 2022. The Author(s).

PY - 2022

Y1 - 2022

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.

U2 - 10.1038/s42003-022-03978-6

DO - 10.1038/s42003-022-03978-6

M3 - Journal article

C2 - 36203093

AN - SCOPUS:85139349547

VL - 5

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

M1 - 1061

ER -

ID: 325633845