RAD51B in familial breast cancer

Liisa M. Pelttari; Sofia Khan; Mikko Vuorela; Johanna I. Kiiski; Sara Vilske; Viivi Nevanlinna; Salla Ranta; Johanna Schleutker; Robert Winqvist; Anne Kallioniemi; Thilo Dörk; Natalia V. Bogdanova; Jonine Figueroa; Paul D.P. Pharoah; Marjanka K. Schmidt; Alison M. Dunning; Montserrat García-Closas; Manjeet K. Bolla; Joe Dennis; Kyriaki Michailidou; Qin Wang; John L. Hopper; Melissa C. Southey; Efraim H. Rosenberg; Peter A. Fasching; Matthias W. Beckmann; Julian Peto; Isabel dos-Santos-Silva; Elinor J. Sawyer; Ian Tomlinson; Barbara Burwinkel; Harald Surowy; Pascal Guénel; Thérèse Truong; Stig E. Bojesen; Børge G. Nordestgaard; Javier Benitez; Anna González-Neira; Susan L. Neuhausen; Hoda Anton-Culver; Hermann Brenner; Volker Arndt; Alfons Meindl; Rita K. Schmutzler; Hiltrud Brauch; Thomas Brüning; Annika Lindblom; Sara Margolin; Arto Mannermaa; Jaana M. Hartikainen; Georgia Chenevix-Trench; kConFab/AOCS Investigators; Laurien Van Dyck; Hilde Janssen; Jenny Chang-Claude; Anja Rudolph; Paolo Radice; Paolo Peterlongo; Emily Hallberg; Janet E. Olson; Graham G. Giles; Roger L. Milne; Christopher A. Haiman; Fredrick Schumacher; Jacques Simard; Martine Dumont; Vessela Kristensen; Anne Lise Borresen-Dale; Wei Zheng; Alicia Beeghly-Fadiel; Mervi Grip; Irene L. Andrulis; Gord Glendon; Peter Devilee; Caroline Seynaeve; Maartje J. Hooning; Margriet Collée; Angela Cox; Simon S. Cross; Mitul Shah; Robert N. Luben; Ute Hamann; Diana Torres; Anna Jakubowska; Jan Lubinski; Fergus J. Couch; Drakoulis Yannoukakos; Nick Orr; Anthony Swerdlow; Hatef Darabi; Jingmei Li; Kamila Czene; Per Hall; Douglas F. Easton; Johanna Mattson; Carl Blomqvist; Kristiina Aittomäki; Heli Nevanlinna; Frank Firgaira; Scott Grist; Eric Haan; Ram Seshadri; Pamela Sykes; D. Henderson

doi:10.1371/journal.pone.0153788

RAD51B in familial breast cancer

Liisa M. Pelttari, Sofia Khan, Mikko Vuorela, Johanna I. Kiiski, Sara Vilske, Viivi Nevanlinna, Salla Ranta, Johanna Schleutker, Robert Winqvist, Anne Kallioniemi, Thilo Dörk, Natalia V. Bogdanova, Jonine Figueroa, Paul D.P. Pharoah, Marjanka K. Schmidt, Alison M. Dunning, Montserrat García-Closas, Manjeet K. Bolla, Joe Dennis, Kyriaki MichailidouQin Wang, John L. Hopper, Melissa C. Southey, Efraim H. Rosenberg, Peter A. Fasching, Matthias W. Beckmann, Julian Peto, Isabel dos-Santos-Silva, Elinor J. Sawyer, Ian Tomlinson, Barbara Burwinkel, Harald Surowy, Pascal Guénel, Thérèse Truong, Stig E. Bojesen, Børge G. Nordestgaard, Javier Benitez, Anna González-Neira, Susan L. Neuhausen, Hoda Anton-Culver, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K. Schmutzler, Hiltrud Brauch, Thomas Brüning, Annika Lindblom, Sara Margolin, Arto Mannermaa, Jaana M. Hartikainen, Georgia Chenevix-Trench, kConFab/AOCS Investigators, Laurien Van Dyck, Hilde Janssen, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Paolo Peterlongo, Emily Hallberg, Janet E. Olson, Graham G. Giles, Roger L. Milne, Christopher A. Haiman, Fredrick Schumacher, Jacques Simard, Martine Dumont, Vessela Kristensen, Anne Lise Borresen-Dale, Wei Zheng, Alicia Beeghly-Fadiel, Mervi Grip, Irene L. Andrulis, Gord Glendon, Peter Devilee, Caroline Seynaeve, Maartje J. Hooning, Margriet Collée, Angela Cox, Simon S. Cross, Mitul Shah, Robert N. Luben, Ute Hamann, Diana Torres, Anna Jakubowska, Jan Lubinski, Fergus J. Couch, Drakoulis Yannoukakos, Nick Orr, Anthony Swerdlow, Hatef Darabi, Jingmei Li, Kamila Czene, Per Hall, Douglas F. Easton, Johanna Mattson, Carl Blomqvist, Kristiina Aittomäki, Heli Nevanlinna, Frank Firgaira, Scott Grist, Eric Haan, Ram Seshadri, Pamela Sykes, D. Henderson

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Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 × 10^-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 10^-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

Original language	English
Article number	e0153788
Number of pages	18
Journal	PLoS One
Volume	11
Issue number	5
DOIs	https://doi.org/10.1371/journal.pone.0153788
Publication status	Published - 5 May 2016

Bibliographical note

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Keywords

RAD51B
breast cancer
familial breast cancer
Finland
Finnish people
Genetic causes of cancer
Variant genotypes
Introns
Ovarian cancer
Haplotypes

UN SDGs

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

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Cite this

Pelttari, L. M., Khan, S., Vuorela, M., Kiiski, J. I., Vilske, S., Nevanlinna, V., Ranta, S., Schleutker, J., Winqvist, R., Kallioniemi, A., Dörk, T., Bogdanova, N. V., Figueroa, J., Pharoah, P. D. P., Schmidt, M. K., Dunning, A. M., García-Closas, M., Bolla, M. K., Dennis, J., ... Henderson, D. (2016). RAD51B in familial breast cancer. PLoS One, 11(5), Article e0153788. https://doi.org/10.1371/journal.pone.0153788

@article{084222c4014943a69b6c4758c6fe5187,

title = "RAD51B in familial breast cancer",

abstract = "Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 × 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.",

keywords = "RAD51B, breast cancer, familial breast cancer, Finland, Finnish people, Genetic causes of cancer, Variant genotypes, Introns, Ovarian cancer, Haplotypes",

author = "Pelttari, {Liisa M.} and Sofia Khan and Mikko Vuorela and Kiiski, {Johanna I.} and Sara Vilske and Viivi Nevanlinna and Salla Ranta and Johanna Schleutker and Robert Winqvist and Anne Kallioniemi and Thilo D{\"o}rk and Bogdanova, {Natalia V.} and Jonine Figueroa and Pharoah, {Paul D.P.} and Schmidt, {Marjanka K.} and Dunning, {Alison M.} and Montserrat Garc{\'i}a-Closas and Bolla, {Manjeet K.} and Joe Dennis and Kyriaki Michailidou and Qin Wang and Hopper, {John L.} and Southey, {Melissa C.} and Rosenberg, {Efraim H.} and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Julian Peto and Isabel dos-Santos-Silva and Sawyer, {Elinor J.} and Ian Tomlinson and Barbara Burwinkel and Harald Surowy and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Javier Benitez and Anna Gonz{\'a}lez-Neira and Neuhausen, {Susan L.} and Hoda Anton-Culver and Hermann Brenner and Volker Arndt and Alfons Meindl and Schmutzler, {Rita K.} and Hiltrud Brauch and Thomas Br{\"u}ning and Annika Lindblom and Sara Margolin and Arto Mannermaa and Hartikainen, {Jaana M.} and Georgia Chenevix-Trench and {kConFab/AOCS Investigators} and {Van Dyck}, Laurien and Hilde Janssen and Jenny Chang-Claude and Anja Rudolph and Paolo Radice and Paolo Peterlongo and Emily Hallberg and Olson, {Janet E.} and Giles, {Graham G.} and Milne, {Roger L.} and Haiman, {Christopher A.} and Fredrick Schumacher and Jacques Simard and Martine Dumont and Vessela Kristensen and Borresen-Dale, {Anne Lise} and Wei Zheng and Alicia Beeghly-Fadiel and Mervi Grip and Andrulis, {Irene L.} and Gord Glendon and Peter Devilee and Caroline Seynaeve and Hooning, {Maartje J.} and Margriet Coll{\'e}e and Angela Cox and Cross, {Simon S.} and Mitul Shah and Luben, {Robert N.} and Ute Hamann and Diana Torres and Anna Jakubowska and Jan Lubinski and Couch, {Fergus J.} and Drakoulis Yannoukakos and Nick Orr and Anthony Swerdlow and Hatef Darabi and Jingmei Li and Kamila Czene and Per Hall and Easton, {Douglas F.} and Johanna Mattson and Carl Blomqvist and Kristiina Aittom{\"a}ki and Heli Nevanlinna and Morteza Aghmesheh and David Amor and Lesley Andrews and Yoland Antill and Shane Armitage and Leanne Arnold and Rosemary Balleine and Agnes Bankier and Patti Bastick and Jonathan Beesley and John Beilby and Barbara Bennett and Ian Bennett and Geoffrey Berry and Anneke Blackburn and Michael Bogwitz and Meagan Brennan and Melissa Brown and Michael Buckley and Matthew Burgess and Jo Burke and Phyllis Butow and Keith Byron and David Callen and Ian Campbell and Deepa Chauhan and Alice Christian and Christine Clarke and Alison Colley and Dick Cotton and Ashley Crook and James Cui and Bronwyn Culling and Margaret Cummings and Sarah-Jane Dawson and Anna DeFazio and Martin Delatycki and Rebecca Dickson and Joanne Dixon and Alexander Dobrovic and Tracy Dudding and Ted Edkins and Stacey Edwards and Maurice Eisenbruch and Gelareh Farshid and Susan Fawcett and Andrew Fellows and Georgina Fenton and Michael Field and Frank Firgaira and James Flanagan and Jean Fleming and Peter Fong and John Forbes and Stephen Fox and Juliet French and Michael Friedlander and Clara Gaff and Mac Gardner and Mike Gattas and Peter George and Grantley Gill and Jack Goldblatt and Sian Greening and Scott Grist and Eric Haan and Kate Hardie and Marion Harris and Stewart Hart and Nick Hayward and Sue Healey and Louise Heiniger and Evelyn Humphrey and Clare Hunt and Paul James and Mark Jenkins and Alison Jones and Rick Kefford and Alexa Kidd and Belinda Kiely and Judy Kirk and Jessica Koehler and James Kollias and Serguei Kovalenko and Sunil Lakhani and Amanda Leaming and Jennifer Leary and Jacqueline Lim and Geoff Lindeman and Lara Lipton and Liz Lobb and Graham Mann and Deborah Marsh and McLachlan, {Sue Anne} and Bettina Meiser and Cliff Meldrum and Gillian Mitchell and Beth Newman and Sophie Nightingale and Shona O'Connell and Imeldao O'Loughlin and Richard Osborne and Nick Pachter and Briony Patterson and Lester Peters and Kelly Phillips and Melanie Price and Lynne Purser and Tony Reeve and Jeanne Reeve and Robert Richards and Edwina Rickard and Bridget Robinson and Barney Rudzki and Mona Saleh and Elizabeth Salisbury and Joe Sambrook and Christobel Saunders and Jodi Saunus and Robyn Sayer and Elizabeth Scott and Rodney Scott and Clare Scott and Ram Seshadri and Adrienne Sexton and Raghwa Sharma and Andrew Shelling and Peter Simpson and Amanda Spurdle and Graeme Suthers and Pamela Sykes and Donna Taylor and Jessica Taylor and Benjamin Thierry and Ella Thompson and Heather Thorne and Sharron Townshend and Alison Trainer and Lan Tran and Kathy Tucker and Janet Tyler and Jane Visvader and Logan Walker and Ian Walpole and Robin Ward and Paul Waring and Bev Warner and Graham Warren and Rachael Williams and Judy Wilson and F. Kirsten and Kathy Wu and Young, {Mary Ann} and D. Henderson",

note = "This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.",

year = "2016",

month = may,

day = "5",

doi = "10.1371/journal.pone.0153788",

language = "English",

volume = "11",

journal = "PLoS One",

issn = "1932-6203",

publisher = "PlosOne",

number = "5",

}

Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Dörk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, García-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guénel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, González-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Brüning, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, kConFab/AOCS Investigators, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Dumont, M, Kristensen, V, Borresen-Dale, AL, Zheng, W, Beeghly-Fadiel, A, Grip, M, Andrulis, IL, Glendon, G, Devilee, P, Seynaeve, C, Hooning, MJ, Collée, M, Cox, A, Cross, SS, Shah, M, Luben, RN, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Couch, FJ, Yannoukakos, D, Orr, N, Swerdlow, A, Darabi, H, Li, J, Czene, K, Hall, P, Easton, DF, Mattson, J, Blomqvist, C, Aittomäki, K, Nevanlinna, H, Firgaira, F, Grist, S, Haan, E, Seshadri, R, Sykes, P & Henderson, D 2016, 'RAD51B in familial breast cancer', PLoS One, vol. 11, no. 5, e0153788. https://doi.org/10.1371/journal.pone.0153788

TY - JOUR

T1 - RAD51B in familial breast cancer

AU - Pelttari, Liisa M.

AU - Khan, Sofia

AU - Vuorela, Mikko

AU - Kiiski, Johanna I.

AU - Vilske, Sara

AU - Nevanlinna, Viivi

AU - Ranta, Salla

AU - Schleutker, Johanna

AU - Winqvist, Robert

AU - Kallioniemi, Anne

AU - Dörk, Thilo

AU - Bogdanova, Natalia V.

AU - Figueroa, Jonine

AU - Pharoah, Paul D.P.

AU - Schmidt, Marjanka K.

AU - Dunning, Alison M.

AU - García-Closas, Montserrat

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Wang, Qin

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Rosenberg, Efraim H.

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Peto, Julian

AU - dos-Santos-Silva, Isabel

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Surowy, Harald

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Benitez, Javier

AU - González-Neira, Anna

AU - Neuhausen, Susan L.

AU - Anton-Culver, Hoda

AU - Brenner, Hermann

AU - Arndt, Volker

AU - Meindl, Alfons

AU - Schmutzler, Rita K.

AU - Brauch, Hiltrud

AU - Brüning, Thomas

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Hartikainen, Jaana M.

AU - Chenevix-Trench, Georgia

AU - kConFab/AOCS Investigators

AU - Van Dyck, Laurien

AU - Janssen, Hilde

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Hallberg, Emily

AU - Olson, Janet E.

AU - Giles, Graham G.

AU - Milne, Roger L.

AU - Haiman, Christopher A.

AU - Schumacher, Fredrick

AU - Simard, Jacques

AU - Dumont, Martine

AU - Kristensen, Vessela

AU - Borresen-Dale, Anne Lise

AU - Zheng, Wei

AU - Beeghly-Fadiel, Alicia

AU - Grip, Mervi

AU - Andrulis, Irene L.

AU - Glendon, Gord

AU - Devilee, Peter

AU - Seynaeve, Caroline

AU - Hooning, Maartje J.

AU - Collée, Margriet

AU - Cox, Angela

AU - Cross, Simon S.

AU - Shah, Mitul

AU - Luben, Robert N.

AU - Hamann, Ute

AU - Torres, Diana

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Couch, Fergus J.

AU - Yannoukakos, Drakoulis

AU - Orr, Nick

AU - Swerdlow, Anthony

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Czene, Kamila

AU - Hall, Per

AU - Easton, Douglas F.

AU - Mattson, Johanna

AU - Blomqvist, Carl

AU - Aittomäki, Kristiina

AU - Nevanlinna, Heli

AU - Aghmesheh, Morteza

AU - Amor, David

AU - Andrews, Lesley

AU - Antill, Yoland

AU - Armitage, Shane

AU - Arnold, Leanne

AU - Balleine, Rosemary

AU - Bankier, Agnes

AU - Bastick, Patti

AU - Beesley, Jonathan

AU - Beilby, John

AU - Bennett, Barbara

AU - Bennett, Ian

AU - Berry, Geoffrey

AU - Blackburn, Anneke

AU - Bogwitz, Michael

AU - Brennan, Meagan

AU - Brown, Melissa

AU - Buckley, Michael

AU - Burgess, Matthew

AU - Burke, Jo

AU - Butow, Phyllis

AU - Byron, Keith

AU - Callen, David

AU - Campbell, Ian

AU - Chauhan, Deepa

AU - Christian, Alice

AU - Clarke, Christine

AU - Colley, Alison

AU - Cotton, Dick

AU - Crook, Ashley

AU - Cui, James

AU - Culling, Bronwyn

AU - Cummings, Margaret

AU - Dawson, Sarah-Jane

AU - DeFazio, Anna

AU - Delatycki, Martin

AU - Dickson, Rebecca

AU - Dixon, Joanne

AU - Dobrovic, Alexander

AU - Dudding, Tracy

AU - Edkins, Ted

AU - Edwards, Stacey

AU - Eisenbruch, Maurice

AU - Farshid, Gelareh

AU - Fawcett, Susan

AU - Fellows, Andrew

AU - Fenton, Georgina

AU - Field, Michael

AU - Firgaira, Frank

AU - Flanagan, James

AU - Fleming, Jean

AU - Fong, Peter

AU - Forbes, John

AU - Fox, Stephen

AU - French, Juliet

AU - Friedlander, Michael

AU - Gaff, Clara

AU - Gardner, Mac

AU - Gattas, Mike

AU - George, Peter

AU - Gill, Grantley

AU - Goldblatt, Jack

AU - Greening, Sian

AU - Grist, Scott

AU - Haan, Eric

AU - Hardie, Kate

AU - Harris, Marion

AU - Hart, Stewart

AU - Hayward, Nick

AU - Healey, Sue

AU - Heiniger, Louise

AU - Humphrey, Evelyn

AU - Hunt, Clare

AU - James, Paul

AU - Jenkins, Mark

AU - Jones, Alison

AU - Kefford, Rick

AU - Kidd, Alexa

AU - Kiely, Belinda

AU - Kirk, Judy

AU - Koehler, Jessica

AU - Kollias, James

AU - Kovalenko, Serguei

AU - Lakhani, Sunil

AU - Leaming, Amanda

AU - Leary, Jennifer

AU - Lim, Jacqueline

AU - Lindeman, Geoff

AU - Lipton, Lara

AU - Lobb, Liz

AU - Mann, Graham

AU - Marsh, Deborah

AU - McLachlan, Sue Anne

AU - Meiser, Bettina

AU - Meldrum, Cliff

AU - Mitchell, Gillian

AU - Newman, Beth

AU - Nightingale, Sophie

AU - O'Connell, Shona

AU - O'Loughlin, Imeldao

AU - Osborne, Richard

AU - Pachter, Nick

AU - Patterson, Briony

AU - Peters, Lester

AU - Phillips, Kelly

AU - Price, Melanie

AU - Purser, Lynne

AU - Reeve, Tony

AU - Reeve, Jeanne

AU - Richards, Robert

AU - Rickard, Edwina

AU - Robinson, Bridget

AU - Rudzki, Barney

AU - Saleh, Mona

AU - Salisbury, Elizabeth

AU - Sambrook, Joe

AU - Saunders, Christobel

AU - Saunus, Jodi

AU - Sayer, Robyn

AU - Scott, Elizabeth

AU - Scott, Rodney

AU - Scott, Clare

AU - Seshadri, Ram

AU - Sexton, Adrienne

AU - Sharma, Raghwa

AU - Shelling, Andrew

AU - Simpson, Peter

AU - Spurdle, Amanda

AU - Suthers, Graeme

AU - Sykes, Pamela

AU - Taylor, Donna

AU - Taylor, Jessica

AU - Thierry, Benjamin

AU - Thompson, Ella

AU - Thorne, Heather

AU - Townshend, Sharron

AU - Trainer, Alison

AU - Tran, Lan

AU - Tucker, Kathy

AU - Tyler, Janet

AU - Visvader, Jane

AU - Walker, Logan

AU - Walpole, Ian

AU - Ward, Robin

AU - Waring, Paul

AU - Warner, Bev

AU - Warren, Graham

AU - Williams, Rachael

AU - Wilson, Judy

AU - Kirsten, F.

AU - Wu, Kathy

AU - Young, Mary Ann

AU - Henderson, D.

N1 - This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

PY - 2016/5/5

Y1 - 2016/5/5

N2 - Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 × 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

AB - Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 × 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 × 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.

KW - RAD51B

KW - breast cancer

KW - familial breast cancer

KW - Finland

KW - Finnish people

KW - Genetic causes of cancer

KW - Variant genotypes

KW - Introns

KW - Ovarian cancer

KW - Haplotypes

UR - http://www.scopus.com/inward/record.url?scp=85023753787&partnerID=8YFLogxK

UR - http://purl.org/au-research/grants/NHMRC/199600

UR - http://purl.org/au-research/grants/NHMRC/400281

UR - http://purl.org/au-research/grants/NHMRC/400413

UR - http://purl.org/au-research/grants/NHMRC/209057

UR - http://purl.org/au-research/grants/NHMRC/251553

UR - http://purl.org/au-research/grants/NHMRC/504711

U2 - 10.1371/journal.pone.0153788

DO - 10.1371/journal.pone.0153788

M3 - Article

C2 - 27149063

AN - SCOPUS:85023753787

SN - 1932-6203

VL - 11

JO - PLoS One

JF - PLoS One

IS - 5

M1 - e0153788

ER -

RAD51B in familial breast cancer

Abstract

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