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

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; Megan Frone; Debra Frost; Judy Garber; Simon A Gayther; Andrea Gehrig; Paul Gesta; Andrew K Godwin; David E Goldgar; Mark H Greene; Eric Hahnen; Christopher R Hake; Ute Hamann; Thomas V O Hansen; Jan Hauke; Julia Hentschel; Natalie Herold; Ellen Honisch; Peter J Hulick; Evgeny N Imyanitov; Claudine Isaacs; Louise Izatt; Angel Izquierdo; Anna Jakubowska; Paul A James; Ramunas Janavicius; Esther M John; Vijai Joseph; Beth Y Karlan; Zoe Kemp; Judy Kirk; Irene Konstantopoulou; Marco Koudijs; Ava Kwong; Yael Laitman; Fiona Lalloo; Christine Lasset; Charlotte Lautrup; Conxi Lazaro; Clémentine Legrand; Goska Leslie; Fabienne Lesueur; Phuong L Mai; Siranoush Manoukian; Véronique Mari; John W M Martens; Lesley McGuffog; Noura Mebirouk; Alfons Meindl; Austin Miller; Marco Montagna; Lidia Moserle; Emmanuelle Mouret-Fourme; Hannah Musgrave; Sophie Nambot; Katherine L Nathanson; Susan L Neuhausen; Heli Nevanlinna; Joanne Ngeow Yuen Yie; Tu Nguyen-Dumont; Liene Nikitina-Zake; Kenneth Offit; Edith Olah; Olufunmilayo I Olopade; Ana Osorio; Claus-Eric Ott; Sue K Park; Michael T Parsons; Inge Sokilde Pedersen; Ana Peixoto; Pedro Perez-Segura; Paolo Peterlongo; Timea Pocza; Paolo Radice; Juliane Ramser; Johanna Rantala; Gustavo C Rodriguez; Karina Rønlund; Efraim H Rosenberg; Maria Rossing; Rita K Schmutzler; Payal D Shah; Saba Sharif; Priyanka Sharma; Lucy E Side; Jacques Simard; Christian F Singer; Katie Snape; Doris Steinemann; Dominique Stoppa-Lyonnet; Christian Sutter; Yen Yen Tan; Manuel R Teixeira; Soo Hwang Teo; Mads Thomassen; Darcy L Thull; Marc Tischkowitz; Amanda E Toland; Alison H Trainer; Vishakha Tripathi; Nadine Tung; Klaartje van Engelen; Elizabeth J van Rensburg; Ana Vega; Alessandra Viel; Lisa Walker; Jeffrey N Weitzel; Marike R Wevers; Georgia Chenevix-Trench; Amanda B Spurdle; Antonis C Antoniou; Logan C Walker; GEMO Study Collaborators

doi:10.1038/s42003-022-03978-6

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

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 BradburyJoan 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, Megan Frone, Debra Frost, Judy Garber, Simon A Gayther, Andrea Gehrig, Paul Gesta, Andrew K Godwin, David E Goldgar, Mark H Greene, Eric Hahnen, Christopher R Hake, Ute Hamann, Thomas V O Hansen, Jan Hauke, Julia Hentschel, Natalie Herold, Ellen Honisch, Peter J Hulick, Evgeny N Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul A James, Ramunas Janavicius, Esther M John, Vijai Joseph, Beth Y Karlan, Zoe Kemp, Judy Kirk, Irene Konstantopoulou, Marco Koudijs, Ava Kwong, Yael Laitman, Fiona Lalloo, Christine Lasset, Charlotte Lautrup, Conxi Lazaro, Clémentine Legrand, Goska Leslie, Fabienne Lesueur, Phuong L Mai, Siranoush Manoukian, Véronique Mari, John W M Martens, Lesley McGuffog, Noura Mebirouk, Alfons Meindl, Austin Miller, Marco Montagna, Lidia Moserle, Emmanuelle Mouret-Fourme, Hannah Musgrave, Sophie Nambot, Katherine L Nathanson, Susan L Neuhausen, Heli Nevanlinna, Joanne Ngeow Yuen Yie, Tu Nguyen-Dumont, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I Olopade, Ana Osorio, Claus-Eric Ott, Sue K Park, Michael T Parsons, Inge Sokilde Pedersen, Ana Peixoto, Pedro Perez-Segura, Paolo Peterlongo, Timea Pocza, Paolo Radice, Juliane Ramser, Johanna Rantala, Gustavo C Rodriguez, Karina Rønlund, Efraim H Rosenberg, Maria Rossing, Rita K Schmutzler, Payal D Shah, Saba Sharif, Priyanka Sharma, Lucy E Side, Jacques Simard, Christian F Singer, Katie Snape, Doris Steinemann, Dominique Stoppa-Lyonnet, Christian Sutter, Yen Yen Tan, Manuel R Teixeira, Soo Hwang Teo, Mads Thomassen, Darcy L Thull, Marc Tischkowitz, Amanda E Toland, Alison H Trainer, Vishakha Tripathi, Nadine Tung, Klaartje van Engelen, Elizabeth J van Rensburg, Ana Vega, Alessandra Viel, Lisa Walker, Jeffrey N Weitzel, Marike R Wevers, Georgia Chenevix-Trench, Amanda B Spurdle, Antonis C Antoniou, Logan C Walker^*, GEMO Study Collaborators

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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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.

Originalsprog	Engelsk
Artikelnummer	1061
Tidsskrift	Communications Biology
Vol/bind	5
Udgave nummer	1
Sider (fra-til)	1061
Antal sider	15
ISSN	2399-3642
DOI	https://doi.org/10.1038/s42003-022-03978-6
Status	Udgivet - 6 okt. 2022

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10.1038/s42003-022-03978-6Licens: CC BY 4.0

Hakkaart et al. (2022). Copy number variants as modifiers of breast cancer risk for BRCA1-BRCA2 pathogenic variant carriersForlagets udgivne version, 4,15 MBLicens: CC BY 4.0

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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., ... GEMO Study Collaborators (2022). Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers. Communications Biology, 5(1), 1061. Artikel 1061. https://doi.org/10.1038/s42003-022-03978-6

@article{6f212153d7a243a5868f6828fd1a4981,

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 = "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 Eitan Friedman and Megan Frone and Debra Frost and Judy Garber and Gayther, {Simon A} and Andrea Gehrig and Paul Gesta and Godwin, {Andrew K} and Goldgar, {David E} and Greene, {Mark H} and Eric Hahnen and Hake, {Christopher R} and Ute Hamann and Hansen, {Thomas V O} and Jan Hauke and Julia Hentschel and Natalie Herold and Ellen Honisch and Hulick, {Peter J} and Imyanitov, {Evgeny N} and Claudine Isaacs and Louise Izatt and Angel Izquierdo and Anna Jakubowska and James, {Paul A} and Ramunas Janavicius and John, {Esther M} and Vijai Joseph and Karlan, {Beth Y} and Zoe Kemp and Judy Kirk and Irene Konstantopoulou and Marco Koudijs and Ava Kwong and Yael Laitman and Fiona Lalloo and Christine Lasset and Charlotte Lautrup and Conxi Lazaro and Cl{\'e}mentine Legrand and Goska Leslie and Fabienne Lesueur and Mai, {Phuong L} and Siranoush Manoukian and V{\'e}ronique Mari and Martens, {John W M} and Lesley McGuffog and Noura Mebirouk and Alfons Meindl and Austin Miller and Marco Montagna and Lidia Moserle and Emmanuelle Mouret-Fourme and Hannah Musgrave and Sophie Nambot and Nathanson, {Katherine L} and Neuhausen, {Susan L} and Heli Nevanlinna and Yie, {Joanne Ngeow Yuen} and Tu Nguyen-Dumont and Liene Nikitina-Zake and Kenneth Offit and Edith Olah and Olopade, {Olufunmilayo I} and Ana Osorio and Claus-Eric Ott and Park, {Sue K} and Parsons, {Michael T} and Pedersen, {Inge Sokilde} and Ana Peixoto and Pedro Perez-Segura and Paolo Peterlongo and Timea Pocza and Paolo Radice and Juliane Ramser and Johanna Rantala and Rodriguez, {Gustavo C} and Karina R{\o}nlund and Rosenberg, {Efraim H} and Maria Rossing and Schmutzler, {Rita K} and Shah, {Payal D} and Saba Sharif and Priyanka Sharma and Side, {Lucy E} and Jacques Simard and Singer, {Christian F} and Katie Snape and Doris Steinemann and Dominique Stoppa-Lyonnet and Christian Sutter and Tan, {Yen Yen} and Teixeira, {Manuel R} and Teo, {Soo Hwang} and Mads Thomassen and Thull, {Darcy L} and Marc Tischkowitz and Toland, {Amanda E} and Trainer, {Alison H} and Vishakha Tripathi and Nadine Tung and {van Engelen}, Klaartje and {van Rensburg}, {Elizabeth J} and Ana Vega and Alessandra Viel and Lisa Walker and Weitzel, {Jeffrey N} and Wevers, {Marike R} and Georgia Chenevix-Trench and Spurdle, {Amanda B} and Antoniou, {Antonis C} and Walker, {Logan C} and {GEMO Study Collaborators}",

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

year = "2022",

month = oct,

day = "6",

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

language = "English",

volume = "5",

pages = "1061",

journal = "Communications Biology",

issn = "2399-3642",

publisher = "Nature Publishing Group",

number = "1",

}

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, Friedman, E, Frone, M, Frost, D, Garber, J, Gayther, SA, Gehrig, A, Gesta, P, Godwin, AK, Goldgar, DE, Greene, MH, Hahnen, E, Hake, CR, Hamann, U, Hansen, TVO, Hauke, J, Hentschel, J, Herold, N, Honisch, E, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Izquierdo, A, Jakubowska, A, James, PA, Janavicius, R, John, EM, Joseph, V, Karlan, BY, Kemp, Z, Kirk, J, Konstantopoulou, I, Koudijs, M, Kwong, A, Laitman, Y, Lalloo, F, Lasset, C, Lautrup, C, Lazaro, C, Legrand, C, Leslie, G, Lesueur, F, Mai, PL, Manoukian, S, Mari, V, Martens, JWM, McGuffog, L, Mebirouk, N, Meindl, A, Miller, A, Montagna, M, Moserle, L, Mouret-Fourme, E, Musgrave, H, Nambot, S, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nguyen-Dumont, T, Nikitina-Zake, L, Offit, K, Olah, E, Olopade, OI, Osorio, A, Ott, C-E, Park, SK, Parsons, MT, Pedersen, IS, Peixoto, A, Perez-Segura, P, Peterlongo, P, Pocza, T, Radice, P, Ramser, J, Rantala, J, Rodriguez, GC, Rønlund, K, Rosenberg, EH, Rossing, M, Schmutzler, RK, Shah, PD, Sharif, S, Sharma, P, Side, LE, Simard, J, Singer, CF, Snape, K, Steinemann, D, Stoppa-Lyonnet, D, Sutter, C, Tan, YY, Teixeira, MR, Teo, SH, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Trainer, AH, Tripathi, V, Tung, N, van Engelen, K, van Rensburg, EJ, Vega, A, Viel, A, Walker, L, Weitzel, JN, Wevers, MR, Chenevix-Trench, G, Spurdle, AB, Antoniou, AC, Walker, LC & GEMO Study Collaborators 2022, 'Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers', Communications Biology, bind 5, nr. 1, 1061, s. 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 - 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

AU - Frone, Megan

AU - Frost, Debra

AU - Garber, Judy

AU - Gayther, Simon A

AU - Gehrig, Andrea

AU - Gesta, Paul

AU - Godwin, Andrew K

AU - Goldgar, David E

AU - Greene, Mark H

AU - Hahnen, Eric

AU - Hake, Christopher R

AU - Hamann, Ute

AU - Hansen, Thomas V O

AU - Hauke, Jan

AU - Hentschel, Julia

AU - Herold, Natalie

AU - Honisch, Ellen

AU - Hulick, Peter J

AU - Imyanitov, Evgeny N

AU - Isaacs, Claudine

AU - Izatt, Louise

AU - Izquierdo, Angel

AU - Jakubowska, Anna

AU - James, Paul A

AU - Janavicius, Ramunas

AU - John, Esther M

AU - Joseph, Vijai

AU - Karlan, Beth Y

AU - Kemp, Zoe

AU - Kirk, Judy

AU - Konstantopoulou, Irene

AU - Koudijs, Marco

AU - Kwong, Ava

AU - Laitman, Yael

AU - Lalloo, Fiona

AU - Lasset, Christine

AU - Lautrup, Charlotte

AU - Lazaro, Conxi

AU - Legrand, Clémentine

AU - Leslie, Goska

AU - Lesueur, Fabienne

AU - Mai, Phuong L

AU - Manoukian, Siranoush

AU - Mari, Véronique

AU - Martens, John W M

AU - McGuffog, Lesley

AU - Mebirouk, Noura

AU - Meindl, Alfons

AU - Miller, Austin

AU - Montagna, Marco

AU - Moserle, Lidia

AU - Mouret-Fourme, Emmanuelle

AU - Musgrave, Hannah

AU - Nambot, Sophie

AU - Nathanson, Katherine L

AU - Neuhausen, Susan L

AU - Nevanlinna, Heli

AU - Yie, Joanne Ngeow Yuen

AU - Nguyen-Dumont, Tu

AU - Nikitina-Zake, Liene

AU - Offit, Kenneth

AU - Olah, Edith

AU - Olopade, Olufunmilayo I

AU - Osorio, Ana

AU - Ott, Claus-Eric

AU - Park, Sue K

AU - Parsons, Michael T

AU - Pedersen, Inge Sokilde

AU - Peixoto, Ana

AU - Perez-Segura, Pedro

AU - Peterlongo, Paolo

AU - Pocza, Timea

AU - Radice, Paolo

AU - Ramser, Juliane

AU - Rantala, Johanna

AU - Rodriguez, Gustavo C

AU - Rønlund, Karina

AU - Rosenberg, Efraim H

AU - Rossing, Maria

AU - Schmutzler, Rita K

AU - Shah, Payal D

AU - Sharif, Saba

AU - Sharma, Priyanka

AU - Side, Lucy E

AU - Simard, Jacques

AU - Singer, Christian F

AU - Snape, Katie

AU - Steinemann, Doris

AU - Stoppa-Lyonnet, Dominique

AU - Sutter, Christian

AU - Tan, Yen Yen

AU - Teixeira, Manuel R

AU - Teo, Soo Hwang

AU - Thomassen, Mads

AU - Thull, Darcy L

AU - Tischkowitz, Marc

AU - Toland, Amanda E

AU - Trainer, Alison H

AU - Tripathi, Vishakha

AU - Tung, Nadine

AU - van Engelen, Klaartje

AU - van Rensburg, Elizabeth J

AU - Vega, Ana

AU - Viel, Alessandra

AU - Walker, Lisa

AU - Weitzel, Jeffrey N

AU - Wevers, Marike R

AU - Chenevix-Trench, Georgia

AU - Spurdle, Amanda B

AU - Antoniou, Antonis C

AU - Walker, Logan C

AU - GEMO Study Collaborators

PY - 2022/10/6

Y1 - 2022/10/6

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 - Journal article

C2 - 36203093

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

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