Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Mia M. Gaudet, Karoline B. Kuchenbaecker, Joseph Vijai, Robert J. Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M. Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M. Sinilnikova, Vernon S. Pankratz, Xianshu Wang, Ronald C. Eldridge, Daniel C. Tessier, Daniel Vincent, Francois Bacot & 313 others Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, Florence Coulet, Chrystelle Colas, Florent Soubrier, Paolo Peterlongo, Rita K. Schmutzler, Katherine L. Nathanson, Marion Piedmonte, Christian F. Singer, Mads Thomassen, Johanna Sokolowska, Myriam Bronner, Thomas V O Hansen, Susan L. Neuhausen, Ignacio Blanco, Mark H. Greene, Judith Garber, Jeffrey N. Weitzel, Irene L. Andrulis, David E. Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J. van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H. van der Hout, Carolien M. Kets, Cora M. Aalfs, Juul T. Wijnen, Margreet G E M Ausems, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D. Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E. Porteous, Francesca Damiola, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B. Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M. Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L. Mai, Javier Benitez, Melissa C. Southey, Marjanka K. Schmidt, Peter A. Fasching, Julian Peto, Manjeet K. Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J. Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E. Bojesen, Roger L. Milne, Hermann Brenner, Magdalena Lochmann, Hiltrud Brauch, Yon Dschun Ko, Christian Baisch, Hand Peter Fischer, Thomas Bruening, Beate Pesch, Sylvia Rabstein, Anne Spickenheuer, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G. Giles, Christopher A. Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J. Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Per Hall, Fergus J. Couch, Jacques Simard, David Altshuler, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Kenneth Offit, M. A. Rookus, F. B L Hogervorst, F. E. van Leeuwen, S. Verhoef, M. K. Schmidt, J. L. de Lange, J. M. Collée, A. M W van den Ouweland, M. J. Hooning, C. Seynaeve, C. H M van Deurzen, C. J. van Asperen, J. T. Wijnen, R. A. Tollenaar, P. Devilee, T. C T E F van Cronenburg, C. M. Kets, A. R. Mensenkamp, M. G E M Ausems, R. B. van der Luijt, C. M. Aalfs, T. A M van Os, J. J P Gille, Q. Waisfisz, H. E J Meijers-Heijboer, E. B. Gómez-Garcia, M. J. Blok, J. C. Oosterwijk, A. H. van der Hout, M. J. Mourits, G. H. de Bock, H. F. Vasen, Susan Peock, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, Zosia Miedzybrodzka, Helen Gregory, Patrick Morrison, Lisa Jeffers, Trevor Cole, Kai ren Ong, Jonathan Hoffman, Alan Donaldson, Margaret James, Marc Tischkowitz, Joan Paterson, Amy Taylor, Alexandra Murray, Mark T. Rogers, Emma McCann, M. John Kennedy, David Barton, Mary Porteous, Sarah Drummond, Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill, Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan, Louise Izatt, Chris Jacobs, Caroline Langman, Angela Brady, Huw Dorkins, Athalie Melville, Kashmir Randhawa, Julian Barwell, Julian Adlard, Gemma Serra-Feliu, Ian Ellis, Catherine Houghton, Fiona Lalloo, Jane Taylor, Lucy Side, Alison Male, Cheryl Berlin, Jacqueline Eason, Rebecca Collier, Fiona Douglas, Oonagh Claber, Irene Jobson, Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner, Rosalind A. Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Emma Killick, Sue Martin, Gillian Rea, Anjana Kulkarni, Jackie Cook, Oliver Quarrell, Cathryn Bardsley, Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard, Anna Lehmann, Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley, Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Sophie Giraud, Mélanie Léone, Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw, Brigitte Bressac-de-Paillerets, Olivier Caron, Yves Jean Bignon, Nancy Uhrhammer, Christine Lasset, Valérie Bonadona, Sandrine Handallou, Agnés Hardouin, Pascaline Berthet, Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger, Isabelle Coupier, Pascal Pujol, Jean Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis, Etienne Rouleau, Rosette Lidereau, Henry T. Lynch, Catherine Nogues, Danièle Muller, Jean Pierre Fricker, Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy, Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon, Fanny Coron, Laurence Faivre, Fabienne Prieur, Marine Lebrun, Caroline Kientz, Sandra Fert Ferrer, Marc Frénay, Laurence Vénat-Bouvet, Capucine Delnatte, Isabelle Mortemousque, Henry T. Lynch, Carrie L. Snyder

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10-8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Original languageEnglish
Article numbere1003173
JournalPLoS Genetics
Volume9
Issue number3
DOIs
StatePublished - 2013

Fingerprint

modifiers (genes)
breast neoplasms
mutation
Breast Neoplasms
Mutation
loci
Single Nucleotide Polymorphism
cancer
allele
Genome-Wide Association Study
Alleles
alleles
genome
cancer risk
tumor suppressor genes
Tumor Suppressor Genes
tumor
transcriptional activation
Transcriptional Activation
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Gaudet, M. M., Kuchenbaecker, K. B., Vijai, J., Klein, R. J., Kirchhoff, T., McGuffog, L., ... Snyder, C. L. (2013). Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk. PLoS Genetics, 9(3), [e1003173]. https://doi.org/10.1371/journal.pgen.1003173

Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk. / Gaudet, Mia M.; Kuchenbaecker, Karoline B.; Vijai, Joseph; Klein, Robert J.; Kirchhoff, Tomas; McGuffog, Lesley; Barrowdale, Daniel; Dunning, Alison M.; Lee, Andrew; Dennis, Joe; Healey, Sue; Dicks, Ed; Soucy, Penny; Sinilnikova, Olga M.; Pankratz, Vernon S.; Wang, Xianshu; Eldridge, Ronald C.; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Hogervorst, Frans B L; Peock, Susan; Stoppa-Lyonnet, Dominique; Coulet, Florence; Colas, Chrystelle; Soubrier, Florent; Peterlongo, Paolo; Schmutzler, Rita K.; Nathanson, Katherine L.; Piedmonte, Marion; Singer, Christian F.; Thomassen, Mads; Sokolowska, Johanna; Bronner, Myriam; Hansen, Thomas V O; Neuhausen, Susan L.; Blanco, Ignacio; Greene, Mark H.; Garber, Judith; Weitzel, Jeffrey N.; Andrulis, Irene L.; Goldgar, David E.; D'Andrea, Emma; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; van Rensburg, Elizabeth J.; Arason, Adalgeir; Rennert, Gad; van den Ouweland, Ans M W; van der Hout, Annemarie H.; Kets, Carolien M.; Aalfs, Cora M.; Wijnen, Juul T.; Ausems, Margreet G E M; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Jacobs, Chris; Adlard, Julian; Tischkowitz, Marc; Porteous, Mary E.; Damiola, Francesca; Golmard, Lisa; Barjhoux, Laure; Longy, Michel; Belotti, Muriel; Ferrer, Sandra Fert; Mazoyer, Sylvie; Spurdle, Amanda B.; Manoukian, Siranoush; Barile, Monica; Genuardi, Maurizio; Arnold, Norbert; Meindl, Alfons; Sutter, Christian; Wappenschmidt, Barbara; Domchek, Susan M.; Pfeiler, Georg; Friedman, Eitan; Jensen, Uffe Birk; Robson, Mark; Shah, Sohela; Lazaro, Conxi; Mai, Phuong L.; Benitez, Javier; Southey, Melissa C.; Schmidt, Marjanka K.; Fasching, Peter A.; Peto, Julian; Humphreys, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Sawyer, Elinor J.; Burwinkel, Barbara; Guénel, Pascal; Bojesen, Stig E.; Milne, Roger L.; Brenner, Hermann; Lochmann, Magdalena; Brauch, Hiltrud; Ko, Yon Dschun; Baisch, Christian; Fischer, Hand Peter; Bruening, Thomas; Pesch, Beate; Rabstein, Sylvia; Spickenheuer, Anne; Aittomäki, Kristiina; Dörk, Thilo; Margolin, Sara; Mannermaa, Arto; Lambrechts, Diether; Chang-Claude, Jenny; Radice, Paolo; Giles, Graham G.; Haiman, Christopher A.; Winqvist, Robert; Devillee, Peter; García-Closas, Montserrat; Schoof, Nils; Hooning, Maartje J.; Cox, Angela; Pharoah, Paul D P; Jakubowska, Anna; Orr, Nick; González-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Hall, Per; Couch, Fergus J.; Simard, Jacques; Altshuler, David; Easton, Douglas F.; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Offit, Kenneth; Rookus, M. A.; Hogervorst, F. B L; van Leeuwen, F. E.; Verhoef, S.; Schmidt, M. K.; de Lange, J. L.; Collée, J. M.; van den Ouweland, A. M W; Hooning, M. J.; Seynaeve, C.; van Deurzen, C. H M; van Asperen, C. J.; Wijnen, J. T.; Tollenaar, R. A.; Devilee, P.; van Cronenburg, T. C T E F; Kets, C. M.; Mensenkamp, A. R.; Ausems, M. G E M; van der Luijt, R. B.; Aalfs, C. M.; van Os, T. A M; Gille, J. J P; Waisfisz, Q.; Meijers-Heijboer, H. E J; Gómez-Garcia, E. B.; Blok, M. J.; Oosterwijk, J. C.; van der Hout, A. H.; Mourits, M. J.; de Bock, G. H.; Vasen, H. F.; Peock, Susan; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Miedzybrodzka, Zosia; Gregory, Helen; Morrison, Patrick; Jeffers, Lisa; Cole, Trevor; Ong, Kai ren; Hoffman, Jonathan; Donaldson, Alan; James, Margaret; Tischkowitz, Marc; Paterson, Joan; Taylor, Amy; Murray, Alexandra; Rogers, Mark T.; McCann, Emma; Kennedy, M. John; Barton, David; Porteous, Mary; Drummond, Sarah; Brewer, Carole; Kivuva, Emma; Searle, Anne; Goodman, Selina; Hill, Kathryn; Davidson, Rosemarie; Murday, Victoria; Bradshaw, Nicola; Snadden, Lesley; Longmuir, Mark; Watt, Catherine; Gibson, Sarah; Haque, Eshika; Tobias, Ed; Duncan, Alexis; Izatt, Louise; Jacobs, Chris; Langman, Caroline; Brady, Angela; Dorkins, Huw; Melville, Athalie; Randhawa, Kashmir; Barwell, Julian; Adlard, Julian; Serra-Feliu, Gemma; Ellis, Ian; Houghton, Catherine; Lalloo, Fiona; Taylor, Jane; Side, Lucy; Male, Alison; Berlin, Cheryl; Eason, Jacqueline; Collier, Rebecca; Douglas, Fiona; Claber, Oonagh; Jobson, Irene; Walker, Lisa; McLeod, Diane; Halliday, Dorothy; Durell, Sarah; Stayner, Barbara; Eeles, Rosalind A.; Shanley, Susan; Rahman, Nazneen; Houlston, Richard; Bancroft, Elizabeth; Page, Elizabeth; Ardern-Jones, Audrey; Kohut, Kelly; Wiggins, Jennifer; Castro, Elena; Killick, Emma; Martin, Sue; Rea, Gillian; Kulkarni, Anjana; Cook, Jackie; Quarrell, Oliver; Bardsley, Cathryn; Hodgson, Shirley; Goff, Sheila; Brice, Glen; Winchester, Lizzie; Eddy, Charlotte; Tripathi, Vishakha; Attard, Virginia; Lehmann, Anna; Eccles, Diana; Lucassen, Anneke; Crawford, Gillian; McBride, Donna; Smalley, Sarah; Sinilnikova, Olga; Mazoyer, Sylvie; Damiola, Francesca; Barjhoux, Laure; Verny-Pierre, Carole; Giraud, Sophie; Léone, Mélanie; Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion; Buecher, Bruno; Houdayer, Claude; Moncoutier, Virginie; Belotti, Muriel; Tirapo, Carole; de Pauw, Antoine; Bressac-de-Paillerets, Brigitte; Caron, Olivier; Bignon, Yves Jean; Uhrhammer, Nancy; Lasset, Christine; Bonadona, Valérie; Handallou, Sandrine; Hardouin, Agnés; Berthet, Pascaline; Sobol, Hagay; Bourdon, Violaine; Noguchi, Tetsuro; Remenieras, Audrey; Eisinger, François; Coupier, Isabelle; Pujol, Pascal; Peyrat, Jean Philippe; Fournier, Joëlle; Révillion, Françoise; Vennin, Philippe; Adenis, Claude; Rouleau, Etienne; Lidereau, Rosette; Lynch, Henry T.; Nogues, Catherine; Muller, Danièle; Fricker, Jean Pierre; Barouk-Simonet, Emmanuelle; Bonnet, Françoise; Bubien, Virginie; Sevenet, Nicolas; Longy, Michel; Toulas, Christine; Guimbaud, Rosine; Gladieff, Laurence; Feillel, Viviane; Dreyfus, Hélène; Rebischung, Christine; Peysselon, Magalie; Coron, Fanny; Faivre, Laurence; Prieur, Fabienne; Lebrun, Marine; Kientz, Caroline; Ferrer, Sandra Fert; Frénay, Marc; Vénat-Bouvet, Laurence; Delnatte, Capucine; Mortemousque, Isabelle; Lynch, Henry T.; Snyder, Carrie L.

In: PLoS Genetics, Vol. 9, No. 3, e1003173, 2013.

Research output: Contribution to journalArticle

Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, OM, Pankratz, VS, Wang, X, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Coulet, F, Colas, C, Soubrier, F, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, M, Sokolowska, J, Bronner, M, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, AMW, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C, Mai, PL, Benitez, J, Southey, MC, Schmidt, MK, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q, Michailidou, K, Sawyer, EJ, Burwinkel, B, Guénel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Brauch, H, Ko, YD, Baisch, C, Fischer, HP, Bruening, T, Pesch, B, Rabstein, S, Spickenheuer, A, Aittomäki, K, Dörk, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, García-Closas, M, Schoof, N, Hooning, MJ, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, González-Neira, A, Pita, G, Alonso, MR, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Offit, K, Rookus, MA, Hogervorst, FBL, van Leeuwen, FE, Verhoef, S, Schmidt, MK, de Lange, JL, Collée, JM, van den Ouweland, AMW, Hooning, MJ, Seynaeve, C, van Deurzen, CHM, van Asperen, CJ, Wijnen, JT, Tollenaar, RA, Devilee, P, van Cronenburg, TCTEF, Kets, CM, Mensenkamp, AR, Ausems, MGEM, van der Luijt, RB, Aalfs, CM, van Os, TAM, Gille, JJP, Waisfisz, Q, Meijers-Heijboer, HEJ, Gómez-Garcia, EB, Blok, MJ, Oosterwijk, JC, van der Hout, AH, Mourits, MJ, de Bock, GH, Vasen, HF, Peock, S, Frost, D, Ellis, S, Fineberg, E, Platte, R, Miedzybrodzka, Z, Gregory, H, Morrison, P, Jeffers, L, Cole, T, Ong, KR, Hoffman, J, Donaldson, A, James, M, Tischkowitz, M, Paterson, J, Taylor, A, Murray, A, Rogers, MT, McCann, E, Kennedy, MJ, Barton, D, Porteous, M, Drummond, S, Brewer, C, Kivuva, E, Searle, A, Goodman, S, Hill, K, Davidson, R, Murday, V, Bradshaw, N, Snadden, L, Longmuir, M, Watt, C, Gibson, S, Haque, E, Tobias, E, Duncan, A, Izatt, L, Jacobs, C, Langman, C, Brady, A, Dorkins, H, Melville, A, Randhawa, K, Barwell, J, Adlard, J, Serra-Feliu, G, Ellis, I, Houghton, C, Lalloo, F, Taylor, J, Side, L, Male, A, Berlin, C, Eason, J, Collier, R, Douglas, F, Claber, O, Jobson, I, Walker, L, McLeod, D, Halliday, D, Durell, S, Stayner, B, Eeles, RA, Shanley, S, Rahman, N, Houlston, R, Bancroft, E, Page, E, Ardern-Jones, A, Kohut, K, Wiggins, J, Castro, E, Killick, E, Martin, S, Rea, G, Kulkarni, A, Cook, J, Quarrell, O, Bardsley, C, Hodgson, S, Goff, S, Brice, G, Winchester, L, Eddy, C, Tripathi, V, Attard, V, Lehmann, A, Eccles, D, Lucassen, A, Crawford, G, McBride, D, Smalley, S, Sinilnikova, O, Mazoyer, S, Damiola, F, Barjhoux, L, Verny-Pierre, C, Giraud, S, Léone, M, Stoppa-Lyonnet, D, Gauthier-Villars, M, Buecher, B, Houdayer, C, Moncoutier, V, Belotti, M, Tirapo, C, de Pauw, A, Bressac-de-Paillerets, B, Caron, O, Bignon, YJ, Uhrhammer, N, Lasset, C, Bonadona, V, Handallou, S, Hardouin, A, Berthet, P, Sobol, H, Bourdon, V, Noguchi, T, Remenieras, A, Eisinger, F, Coupier, I, Pujol, P, Peyrat, JP, Fournier, J, Révillion, F, Vennin, P, Adenis, C, Rouleau, E, Lidereau, R, Lynch, HT, Nogues, C, Muller, D, Fricker, JP, Barouk-Simonet, E, Bonnet, F, Bubien, V, Sevenet, N, Longy, M, Toulas, C, Guimbaud, R, Gladieff, L, Feillel, V, Dreyfus, H, Rebischung, C, Peysselon, M, Coron, F, Faivre, L, Prieur, F, Lebrun, M, Kientz, C, Ferrer, SF, Frénay, M, Vénat-Bouvet, L, Delnatte, C, Mortemousque, I, Lynch, HT & Snyder, CL 2013, 'Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk', PLoS Genetics, vol. 9, no. 3, e1003173. https://doi.org/10.1371/journal.pgen.1003173
Gaudet MM, Kuchenbaecker KB, Vijai J, Klein RJ, Kirchhoff T, McGuffog L et al. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk. PLoS Genetics. 2013;9(3). e1003173. https://doi.org/10.1371/journal.pgen.1003173
Gaudet, Mia M. ; Kuchenbaecker, Karoline B. ; Vijai, Joseph ; Klein, Robert J. ; Kirchhoff, Tomas ; McGuffog, Lesley ; Barrowdale, Daniel ; Dunning, Alison M. ; Lee, Andrew ; Dennis, Joe ; Healey, Sue ; Dicks, Ed ; Soucy, Penny ; Sinilnikova, Olga M. ; Pankratz, Vernon S. ; Wang, Xianshu ; Eldridge, Ronald C. ; Tessier, Daniel C. ; Vincent, Daniel ; Bacot, Francois ; Hogervorst, Frans B L ; Peock, Susan ; Stoppa-Lyonnet, Dominique ; Coulet, Florence ; Colas, Chrystelle ; Soubrier, Florent ; Peterlongo, Paolo ; Schmutzler, Rita K. ; Nathanson, Katherine L. ; Piedmonte, Marion ; Singer, Christian F. ; Thomassen, Mads ; Sokolowska, Johanna ; Bronner, Myriam ; Hansen, Thomas V O ; Neuhausen, Susan L. ; Blanco, Ignacio ; Greene, Mark H. ; Garber, Judith ; Weitzel, Jeffrey N. ; Andrulis, Irene L. ; Goldgar, David E. ; D'Andrea, Emma ; Caldes, Trinidad ; Nevanlinna, Heli ; Osorio, Ana ; van Rensburg, Elizabeth J. ; Arason, Adalgeir ; Rennert, Gad ; van den Ouweland, Ans M W ; van der Hout, Annemarie H. ; Kets, Carolien M. ; Aalfs, Cora M. ; Wijnen, Juul T. ; Ausems, Margreet G E M ; Frost, Debra ; Ellis, Steve ; Fineberg, Elena ; Platte, Radka ; Evans, D. Gareth ; Jacobs, Chris ; Adlard, Julian ; Tischkowitz, Marc ; Porteous, Mary E. ; Damiola, Francesca ; Golmard, Lisa ; Barjhoux, Laure ; Longy, Michel ; Belotti, Muriel ; Ferrer, Sandra Fert ; Mazoyer, Sylvie ; Spurdle, Amanda B. ; Manoukian, Siranoush ; Barile, Monica ; Genuardi, Maurizio ; Arnold, Norbert ; Meindl, Alfons ; Sutter, Christian ; Wappenschmidt, Barbara ; Domchek, Susan M. ; Pfeiler, Georg ; Friedman, Eitan ; Jensen, Uffe Birk ; Robson, Mark ; Shah, Sohela ; Lazaro, Conxi ; Mai, Phuong L. ; Benitez, Javier ; Southey, Melissa C. ; Schmidt, Marjanka K. ; Fasching, Peter A. ; Peto, Julian ; Humphreys, Manjeet K. ; Wang, Qin ; Michailidou, Kyriaki ; Sawyer, Elinor J. ; Burwinkel, Barbara ; Guénel, Pascal ; Bojesen, Stig E. ; Milne, Roger L. ; Brenner, Hermann ; Lochmann, Magdalena ; Brauch, Hiltrud ; Ko, Yon Dschun ; Baisch, Christian ; Fischer, Hand Peter ; Bruening, Thomas ; Pesch, Beate ; Rabstein, Sylvia ; Spickenheuer, Anne ; Aittomäki, Kristiina ; Dörk, Thilo ; Margolin, Sara ; Mannermaa, Arto ; Lambrechts, Diether ; Chang-Claude, Jenny ; Radice, Paolo ; Giles, Graham G. ; Haiman, Christopher A. ; Winqvist, Robert ; Devillee, Peter ; García-Closas, Montserrat ; Schoof, Nils ; Hooning, Maartje J. ; Cox, Angela ; Pharoah, Paul D P ; Jakubowska, Anna ; Orr, Nick ; González-Neira, Anna ; Pita, Guillermo ; Alonso, M. Rosario ; Hall, Per ; Couch, Fergus J. ; Simard, Jacques ; Altshuler, David ; Easton, Douglas F. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Offit, Kenneth ; Rookus, M. A. ; Hogervorst, F. B L ; van Leeuwen, F. E. ; Verhoef, S. ; Schmidt, M. K. ; de Lange, J. L. ; Collée, J. M. ; van den Ouweland, A. M W ; Hooning, M. J. ; Seynaeve, C. ; van Deurzen, C. H M ; van Asperen, C. J. ; Wijnen, J. T. ; Tollenaar, R. A. ; Devilee, P. ; van Cronenburg, T. C T E F ; Kets, C. M. ; Mensenkamp, A. R. ; Ausems, M. G E M ; van der Luijt, R. B. ; Aalfs, C. M. ; van Os, T. A M ; Gille, J. J P ; Waisfisz, Q. ; Meijers-Heijboer, H. E J ; Gómez-Garcia, E. B. ; Blok, M. J. ; Oosterwijk, J. C. ; van der Hout, A. H. ; Mourits, M. J. ; de Bock, G. H. ; Vasen, H. F. ; Peock, Susan ; Frost, Debra ; Ellis, Steve ; Fineberg, Elena ; Platte, Radka ; Miedzybrodzka, Zosia ; Gregory, Helen ; Morrison, Patrick ; Jeffers, Lisa ; Cole, Trevor ; Ong, Kai ren ; Hoffman, Jonathan ; Donaldson, Alan ; James, Margaret ; Tischkowitz, Marc ; Paterson, Joan ; Taylor, Amy ; Murray, Alexandra ; Rogers, Mark T. ; McCann, Emma ; Kennedy, M. John ; Barton, David ; Porteous, Mary ; Drummond, Sarah ; Brewer, Carole ; Kivuva, Emma ; Searle, Anne ; Goodman, Selina ; Hill, Kathryn ; Davidson, Rosemarie ; Murday, Victoria ; Bradshaw, Nicola ; Snadden, Lesley ; Longmuir, Mark ; Watt, Catherine ; Gibson, Sarah ; Haque, Eshika ; Tobias, Ed ; Duncan, Alexis ; Izatt, Louise ; Jacobs, Chris ; Langman, Caroline ; Brady, Angela ; Dorkins, Huw ; Melville, Athalie ; Randhawa, Kashmir ; Barwell, Julian ; Adlard, Julian ; Serra-Feliu, Gemma ; Ellis, Ian ; Houghton, Catherine ; Lalloo, Fiona ; Taylor, Jane ; Side, Lucy ; Male, Alison ; Berlin, Cheryl ; Eason, Jacqueline ; Collier, Rebecca ; Douglas, Fiona ; Claber, Oonagh ; Jobson, Irene ; Walker, Lisa ; McLeod, Diane ; Halliday, Dorothy ; Durell, Sarah ; Stayner, Barbara ; Eeles, Rosalind A. ; Shanley, Susan ; Rahman, Nazneen ; Houlston, Richard ; Bancroft, Elizabeth ; Page, Elizabeth ; Ardern-Jones, Audrey ; Kohut, Kelly ; Wiggins, Jennifer ; Castro, Elena ; Killick, Emma ; Martin, Sue ; Rea, Gillian ; Kulkarni, Anjana ; Cook, Jackie ; Quarrell, Oliver ; Bardsley, Cathryn ; Hodgson, Shirley ; Goff, Sheila ; Brice, Glen ; Winchester, Lizzie ; Eddy, Charlotte ; Tripathi, Vishakha ; Attard, Virginia ; Lehmann, Anna ; Eccles, Diana ; Lucassen, Anneke ; Crawford, Gillian ; McBride, Donna ; Smalley, Sarah ; Sinilnikova, Olga ; Mazoyer, Sylvie ; Damiola, Francesca ; Barjhoux, Laure ; Verny-Pierre, Carole ; Giraud, Sophie ; Léone, Mélanie ; Stoppa-Lyonnet, Dominique ; Gauthier-Villars, Marion ; Buecher, Bruno ; Houdayer, Claude ; Moncoutier, Virginie ; Belotti, Muriel ; Tirapo, Carole ; de Pauw, Antoine ; Bressac-de-Paillerets, Brigitte ; Caron, Olivier ; Bignon, Yves Jean ; Uhrhammer, Nancy ; Lasset, Christine ; Bonadona, Valérie ; Handallou, Sandrine ; Hardouin, Agnés ; Berthet, Pascaline ; Sobol, Hagay ; Bourdon, Violaine ; Noguchi, Tetsuro ; Remenieras, Audrey ; Eisinger, François ; Coupier, Isabelle ; Pujol, Pascal ; Peyrat, Jean Philippe ; Fournier, Joëlle ; Révillion, Françoise ; Vennin, Philippe ; Adenis, Claude ; Rouleau, Etienne ; Lidereau, Rosette ; Lynch, Henry T. ; Nogues, Catherine ; Muller, Danièle ; Fricker, Jean Pierre ; Barouk-Simonet, Emmanuelle ; Bonnet, Françoise ; Bubien, Virginie ; Sevenet, Nicolas ; Longy, Michel ; Toulas, Christine ; Guimbaud, Rosine ; Gladieff, Laurence ; Feillel, Viviane ; Dreyfus, Hélène ; Rebischung, Christine ; Peysselon, Magalie ; Coron, Fanny ; Faivre, Laurence ; Prieur, Fabienne ; Lebrun, Marine ; Kientz, Caroline ; Ferrer, Sandra Fert ; Frénay, Marc ; Vénat-Bouvet, Laurence ; Delnatte, Capucine ; Mortemousque, Isabelle ; Lynch, Henry T. ; Snyder, Carrie L. / Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk. In: PLoS Genetics. 2013 ; Vol. 9, No. 3.
@article{b7d5458fe42e43608fca54fc70e763bf,
title = "Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk",
abstract = "Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95{\%} CI 0.80-0.90, P = 3.9×10-8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.",
author = "Gaudet, {Mia M.} and Kuchenbaecker, {Karoline B.} and Joseph Vijai and Klein, {Robert J.} and Tomas Kirchhoff and Lesley McGuffog and Daniel Barrowdale and Dunning, {Alison M.} and Andrew Lee and Joe Dennis and Sue Healey and Ed Dicks and Penny Soucy and Sinilnikova, {Olga M.} and Pankratz, {Vernon S.} and Xianshu Wang and Eldridge, {Ronald C.} and Tessier, {Daniel C.} and Daniel Vincent and Francois Bacot and Hogervorst, {Frans B L} and Susan Peock and Dominique Stoppa-Lyonnet and Florence Coulet and Chrystelle Colas and Florent Soubrier and Paolo Peterlongo and Schmutzler, {Rita K.} and Nathanson, {Katherine L.} and Marion Piedmonte and Singer, {Christian F.} and Mads Thomassen and Johanna Sokolowska and Myriam Bronner and Hansen, {Thomas V O} and Neuhausen, {Susan L.} and Ignacio Blanco and Greene, {Mark H.} and Judith Garber and Weitzel, {Jeffrey N.} and Andrulis, {Irene L.} and Goldgar, {David E.} and Emma D'Andrea and Trinidad Caldes and Heli Nevanlinna and Ana Osorio and {van Rensburg}, {Elizabeth J.} and Adalgeir Arason and Gad Rennert and {van den Ouweland}, {Ans M W} and {van der Hout}, {Annemarie H.} and Kets, {Carolien M.} and Aalfs, {Cora M.} and Wijnen, {Juul T.} and Ausems, {Margreet G E M} and Debra Frost and Steve Ellis and Elena Fineberg and Radka Platte and Evans, {D. Gareth} and Chris Jacobs and Julian Adlard and Marc Tischkowitz and Porteous, {Mary E.} and Francesca Damiola and Lisa Golmard and Laure Barjhoux and Michel Longy and Muriel Belotti and Ferrer, {Sandra Fert} and Sylvie Mazoyer and Spurdle, {Amanda B.} and Siranoush Manoukian and Monica Barile and Maurizio Genuardi and Norbert Arnold and Alfons Meindl and Christian Sutter and Barbara Wappenschmidt and Domchek, {Susan M.} and Georg Pfeiler and Eitan Friedman and Jensen, {Uffe Birk} and Mark Robson and Sohela Shah and Conxi Lazaro and Mai, {Phuong L.} and Javier Benitez and Southey, {Melissa C.} and Schmidt, {Marjanka K.} and Fasching, {Peter A.} and Julian Peto and Humphreys, {Manjeet K.} and Qin Wang and Kyriaki Michailidou and Sawyer, {Elinor J.} and Barbara Burwinkel and Pascal Gu{\'e}nel and Bojesen, {Stig E.} and Milne, {Roger L.} and Hermann Brenner and Magdalena Lochmann and Hiltrud Brauch and Ko, {Yon Dschun} and Christian Baisch and Fischer, {Hand Peter} and Thomas Bruening and Beate Pesch and Sylvia Rabstein and Anne Spickenheuer and Kristiina Aittom{\"a}ki and Thilo D{\"o}rk and Sara Margolin and Arto Mannermaa and Diether Lambrechts and Jenny Chang-Claude and Paolo Radice and Giles, {Graham G.} and Haiman, {Christopher A.} and Robert Winqvist and Peter Devillee and Montserrat Garc{\'i}a-Closas and Nils Schoof and Hooning, {Maartje J.} and Angela Cox and Pharoah, {Paul D P} and Anna Jakubowska and Nick Orr and Anna Gonz{\'a}lez-Neira and Guillermo Pita and Alonso, {M. Rosario} and Per Hall and Couch, {Fergus J.} and Jacques Simard and David Altshuler and Easton, {Douglas F.} and Georgia Chenevix-Trench and Antoniou, {Antonis C.} and Kenneth Offit and Rookus, {M. A.} and Hogervorst, {F. B L} and {van Leeuwen}, {F. E.} and S. Verhoef and Schmidt, {M. K.} and {de Lange}, {J. L.} and Coll{\'e}e, {J. M.} and {van den Ouweland}, {A. M W} and Hooning, {M. J.} and C. Seynaeve and {van Deurzen}, {C. H M} and {van Asperen}, {C. J.} and Wijnen, {J. T.} and Tollenaar, {R. A.} and P. Devilee and {van Cronenburg}, {T. C T E F} and Kets, {C. M.} and Mensenkamp, {A. R.} and Ausems, {M. G E M} and {van der Luijt}, {R. B.} and Aalfs, {C. M.} and {van Os}, {T. A M} and Gille, {J. J P} and Q. Waisfisz and Meijers-Heijboer, {H. E J} and G{\'o}mez-Garcia, {E. B.} and Blok, {M. J.} and Oosterwijk, {J. C.} and {van der Hout}, {A. H.} and Mourits, {M. J.} and {de Bock}, {G. H.} and Vasen, {H. F.} and Susan Peock and Debra Frost and Steve Ellis and Elena Fineberg and Radka Platte and Zosia Miedzybrodzka and Helen Gregory and Patrick Morrison and Lisa Jeffers and Trevor Cole and Ong, {Kai ren} and Jonathan Hoffman and Alan Donaldson and Margaret James and Marc Tischkowitz and Joan Paterson and Amy Taylor and Alexandra Murray and Rogers, {Mark T.} and Emma McCann and Kennedy, {M. John} and David Barton and Mary Porteous and Sarah Drummond and Carole Brewer and Emma Kivuva and Anne Searle and Selina Goodman and Kathryn Hill and Rosemarie Davidson and Victoria Murday and Nicola Bradshaw and Lesley Snadden and Mark Longmuir and Catherine Watt and Sarah Gibson and Eshika Haque and Ed Tobias and Alexis Duncan and Louise Izatt and Chris Jacobs and Caroline Langman and Angela Brady and Huw Dorkins and Athalie Melville and Kashmir Randhawa and Julian Barwell and Julian Adlard and Gemma Serra-Feliu and Ian Ellis and Catherine Houghton and Fiona Lalloo and Jane Taylor and Lucy Side and Alison Male and Cheryl Berlin and Jacqueline Eason and Rebecca Collier and Fiona Douglas and Oonagh Claber and Irene Jobson and Lisa Walker and Diane McLeod and Dorothy Halliday and Sarah Durell and Barbara Stayner and Eeles, {Rosalind A.} and Susan Shanley and Nazneen Rahman and Richard Houlston and Elizabeth Bancroft and Elizabeth Page and Audrey Ardern-Jones and Kelly Kohut and Jennifer Wiggins and Elena Castro and Emma Killick and Sue Martin and Gillian Rea and Anjana Kulkarni and Jackie Cook and Oliver Quarrell and Cathryn Bardsley and Shirley Hodgson and Sheila Goff and Glen Brice and Lizzie Winchester and Charlotte Eddy and Vishakha Tripathi and Virginia Attard and Anna Lehmann and Diana Eccles and Anneke Lucassen and Gillian Crawford and Donna McBride and Sarah Smalley and Olga Sinilnikova and Sylvie Mazoyer and Francesca Damiola and Laure Barjhoux and Carole Verny-Pierre and Sophie Giraud and M{\'e}lanie L{\'e}one and Dominique Stoppa-Lyonnet and Marion Gauthier-Villars and Bruno Buecher and Claude Houdayer and Virginie Moncoutier and Muriel Belotti and Carole Tirapo and {de Pauw}, Antoine and Brigitte Bressac-de-Paillerets and Olivier Caron and Bignon, {Yves Jean} and Nancy Uhrhammer and Christine Lasset and Val{\'e}rie Bonadona and Sandrine Handallou and Agn{\'e}s Hardouin and Pascaline Berthet and Hagay Sobol and Violaine Bourdon and Tetsuro Noguchi and Audrey Remenieras and Fran{\cc}ois Eisinger and Isabelle Coupier and Pascal Pujol and Peyrat, {Jean Philippe} and Jo{\"e}lle Fournier and Fran{\cc}oise R{\'e}villion and Philippe Vennin and Claude Adenis and Etienne Rouleau and Rosette Lidereau and Lynch, {Henry T.} and Catherine Nogues and Dani{\`e}le Muller and Fricker, {Jean Pierre} and Emmanuelle Barouk-Simonet and Fran{\cc}oise Bonnet and Virginie Bubien and Nicolas Sevenet and Michel Longy and Christine Toulas and Rosine Guimbaud and Laurence Gladieff and Viviane Feillel and H{\'e}l{\`e}ne Dreyfus and Christine Rebischung and Magalie Peysselon and Fanny Coron and Laurence Faivre and Fabienne Prieur and Marine Lebrun and Caroline Kientz and Ferrer, {Sandra Fert} and Marc Fr{\'e}nay and Laurence V{\'e}nat-Bouvet and Capucine Delnatte and Isabelle Mortemousque and Lynch, {Henry T.} and Snyder, {Carrie L.}",
year = "2013",
doi = "10.1371/journal.pgen.1003173",
language = "English",
volume = "9",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

AU - Gaudet, Mia M.

AU - Kuchenbaecker, Karoline B.

AU - Vijai, Joseph

AU - Klein, Robert J.

AU - Kirchhoff, Tomas

AU - McGuffog, Lesley

AU - Barrowdale, Daniel

AU - Dunning, Alison M.

AU - Lee, Andrew

AU - Dennis, Joe

AU - Healey, Sue

AU - Dicks, Ed

AU - Soucy, Penny

AU - Sinilnikova, Olga M.

AU - Pankratz, Vernon S.

AU - Wang, Xianshu

AU - Eldridge, Ronald C.

AU - Tessier, Daniel C.

AU - Vincent, Daniel

AU - Bacot, Francois

AU - Hogervorst, Frans B L

AU - Peock, Susan

AU - Stoppa-Lyonnet, Dominique

AU - Coulet, Florence

AU - Colas, Chrystelle

AU - Soubrier, Florent

AU - Peterlongo, Paolo

AU - Schmutzler, Rita K.

AU - Nathanson, Katherine L.

AU - Piedmonte, Marion

AU - Singer, Christian F.

AU - Thomassen, Mads

AU - Sokolowska, Johanna

AU - Bronner, Myriam

AU - Hansen, Thomas V O

AU - Neuhausen, Susan L.

AU - Blanco, Ignacio

AU - Greene, Mark H.

AU - Garber, Judith

AU - Weitzel, Jeffrey N.

AU - Andrulis, Irene L.

AU - Goldgar, David E.

AU - D'Andrea, Emma

AU - Caldes, Trinidad

AU - Nevanlinna, Heli

AU - Osorio, Ana

AU - van Rensburg, Elizabeth J.

AU - Arason, Adalgeir

AU - Rennert, Gad

AU - van den Ouweland, Ans M W

AU - van der Hout, Annemarie H.

AU - Kets, Carolien M.

AU - Aalfs, Cora M.

AU - Wijnen, Juul T.

AU - Ausems, Margreet G E M

AU - Frost, Debra

AU - Ellis, Steve

AU - Fineberg, Elena

AU - Platte, Radka

AU - Evans, D. Gareth

AU - Jacobs, Chris

AU - Adlard, Julian

AU - Tischkowitz, Marc

AU - Porteous, Mary E.

AU - Damiola, Francesca

AU - Golmard, Lisa

AU - Barjhoux, Laure

AU - Longy, Michel

AU - Belotti, Muriel

AU - Ferrer, Sandra Fert

AU - Mazoyer, Sylvie

AU - Spurdle, Amanda B.

AU - Manoukian, Siranoush

AU - Barile, Monica

AU - Genuardi, Maurizio

AU - Arnold, Norbert

AU - Meindl, Alfons

AU - Sutter, Christian

AU - Wappenschmidt, Barbara

AU - Domchek, Susan M.

AU - Pfeiler, Georg

AU - Friedman, Eitan

AU - Jensen, Uffe Birk

AU - Robson, Mark

AU - Shah, Sohela

AU - Lazaro, Conxi

AU - Mai, Phuong L.

AU - Benitez, Javier

AU - Southey, Melissa C.

AU - Schmidt, Marjanka K.

AU - Fasching, Peter A.

AU - Peto, Julian

AU - Humphreys, Manjeet K.

AU - Wang, Qin

AU - Michailidou, Kyriaki

AU - Sawyer, Elinor J.

AU - Burwinkel, Barbara

AU - Guénel, Pascal

AU - Bojesen, Stig E.

AU - Milne, Roger L.

AU - Brenner, Hermann

AU - Lochmann, Magdalena

AU - Brauch, Hiltrud

AU - Ko, Yon Dschun

AU - Baisch, Christian

AU - Fischer, Hand Peter

AU - Bruening, Thomas

AU - Pesch, Beate

AU - Rabstein, Sylvia

AU - Spickenheuer, Anne

AU - Aittomäki, Kristiina

AU - Dörk, Thilo

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Lambrechts, Diether

AU - Chang-Claude, Jenny

AU - Radice, Paolo

AU - Giles, Graham G.

AU - Haiman, Christopher A.

AU - Winqvist, Robert

AU - Devillee, Peter

AU - García-Closas, Montserrat

AU - Schoof, Nils

AU - Hooning, Maartje J.

AU - Cox, Angela

AU - Pharoah, Paul D P

AU - Jakubowska, Anna

AU - Orr, Nick

AU - González-Neira, Anna

AU - Pita, Guillermo

AU - Alonso, M. Rosario

AU - Hall, Per

AU - Couch, Fergus J.

AU - Simard, Jacques

AU - Altshuler, David

AU - Easton, Douglas F.

AU - Chenevix-Trench, Georgia

AU - Antoniou, Antonis C.

AU - Offit, Kenneth

AU - Rookus, M. A.

AU - Hogervorst, F. B L

AU - van Leeuwen, F. E.

AU - Verhoef, S.

AU - Schmidt, M. K.

AU - de Lange, J. L.

AU - Collée, J. M.

AU - van den Ouweland, A. M W

AU - Hooning, M. J.

AU - Seynaeve, C.

AU - van Deurzen, C. H M

AU - van Asperen, C. J.

AU - Wijnen, J. T.

AU - Tollenaar, R. A.

AU - Devilee, P.

AU - van Cronenburg, T. C T E F

AU - Kets, C. M.

AU - Mensenkamp, A. R.

AU - Ausems, M. G E M

AU - van der Luijt, R. B.

AU - Aalfs, C. M.

AU - van Os, T. A M

AU - Gille, J. J P

AU - Waisfisz, Q.

AU - Meijers-Heijboer, H. E J

AU - Gómez-Garcia, E. B.

AU - Blok, M. J.

AU - Oosterwijk, J. C.

AU - van der Hout, A. H.

AU - Mourits, M. J.

AU - de Bock, G. H.

AU - Vasen, H. F.

AU - Peock, Susan

AU - Frost, Debra

AU - Ellis, Steve

AU - Fineberg, Elena

AU - Platte, Radka

AU - Miedzybrodzka, Zosia

AU - Gregory, Helen

AU - Morrison, Patrick

AU - Jeffers, Lisa

AU - Cole, Trevor

AU - Ong, Kai ren

AU - Hoffman, Jonathan

AU - Donaldson, Alan

AU - James, Margaret

AU - Tischkowitz, Marc

AU - Paterson, Joan

AU - Taylor, Amy

AU - Murray, Alexandra

AU - Rogers, Mark T.

AU - McCann, Emma

AU - Kennedy, M. John

AU - Barton, David

AU - Porteous, Mary

AU - Drummond, Sarah

AU - Brewer, Carole

AU - Kivuva, Emma

AU - Searle, Anne

AU - Goodman, Selina

AU - Hill, Kathryn

AU - Davidson, Rosemarie

AU - Murday, Victoria

AU - Bradshaw, Nicola

AU - Snadden, Lesley

AU - Longmuir, Mark

AU - Watt, Catherine

AU - Gibson, Sarah

AU - Haque, Eshika

AU - Tobias, Ed

AU - Duncan, Alexis

AU - Izatt, Louise

AU - Jacobs, Chris

AU - Langman, Caroline

AU - Brady, Angela

AU - Dorkins, Huw

AU - Melville, Athalie

AU - Randhawa, Kashmir

AU - Barwell, Julian

AU - Adlard, Julian

AU - Serra-Feliu, Gemma

AU - Ellis, Ian

AU - Houghton, Catherine

AU - Lalloo, Fiona

AU - Taylor, Jane

AU - Side, Lucy

AU - Male, Alison

AU - Berlin, Cheryl

AU - Eason, Jacqueline

AU - Collier, Rebecca

AU - Douglas, Fiona

AU - Claber, Oonagh

AU - Jobson, Irene

AU - Walker, Lisa

AU - McLeod, Diane

AU - Halliday, Dorothy

AU - Durell, Sarah

AU - Stayner, Barbara

AU - Eeles, Rosalind A.

AU - Shanley, Susan

AU - Rahman, Nazneen

AU - Houlston, Richard

AU - Bancroft, Elizabeth

AU - Page, Elizabeth

AU - Ardern-Jones, Audrey

AU - Kohut, Kelly

AU - Wiggins, Jennifer

AU - Castro, Elena

AU - Killick, Emma

AU - Martin, Sue

AU - Rea, Gillian

AU - Kulkarni, Anjana

AU - Cook, Jackie

AU - Quarrell, Oliver

AU - Bardsley, Cathryn

AU - Hodgson, Shirley

AU - Goff, Sheila

AU - Brice, Glen

AU - Winchester, Lizzie

AU - Eddy, Charlotte

AU - Tripathi, Vishakha

AU - Attard, Virginia

AU - Lehmann, Anna

AU - Eccles, Diana

AU - Lucassen, Anneke

AU - Crawford, Gillian

AU - McBride, Donna

AU - Smalley, Sarah

AU - Sinilnikova, Olga

AU - Mazoyer, Sylvie

AU - Damiola, Francesca

AU - Barjhoux, Laure

AU - Verny-Pierre, Carole

AU - Giraud, Sophie

AU - Léone, Mélanie

AU - Stoppa-Lyonnet, Dominique

AU - Gauthier-Villars, Marion

AU - Buecher, Bruno

AU - Houdayer, Claude

AU - Moncoutier, Virginie

AU - Belotti, Muriel

AU - Tirapo, Carole

AU - de Pauw, Antoine

AU - Bressac-de-Paillerets, Brigitte

AU - Caron, Olivier

AU - Bignon, Yves Jean

AU - Uhrhammer, Nancy

AU - Lasset, Christine

AU - Bonadona, Valérie

AU - Handallou, Sandrine

AU - Hardouin, Agnés

AU - Berthet, Pascaline

AU - Sobol, Hagay

AU - Bourdon, Violaine

AU - Noguchi, Tetsuro

AU - Remenieras, Audrey

AU - Eisinger, François

AU - Coupier, Isabelle

AU - Pujol, Pascal

AU - Peyrat, Jean Philippe

AU - Fournier, Joëlle

AU - Révillion, Françoise

AU - Vennin, Philippe

AU - Adenis, Claude

AU - Rouleau, Etienne

AU - Lidereau, Rosette

AU - Lynch, Henry T.

AU - Nogues, Catherine

AU - Muller, Danièle

AU - Fricker, Jean Pierre

AU - Barouk-Simonet, Emmanuelle

AU - Bonnet, Françoise

AU - Bubien, Virginie

AU - Sevenet, Nicolas

AU - Longy, Michel

AU - Toulas, Christine

AU - Guimbaud, Rosine

AU - Gladieff, Laurence

AU - Feillel, Viviane

AU - Dreyfus, Hélène

AU - Rebischung, Christine

AU - Peysselon, Magalie

AU - Coron, Fanny

AU - Faivre, Laurence

AU - Prieur, Fabienne

AU - Lebrun, Marine

AU - Kientz, Caroline

AU - Ferrer, Sandra Fert

AU - Frénay, Marc

AU - Vénat-Bouvet, Laurence

AU - Delnatte, Capucine

AU - Mortemousque, Isabelle

AU - Lynch, Henry T.

AU - Snyder, Carrie L.

PY - 2013

Y1 - 2013

N2 - Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10-8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

AB - Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10-8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

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U2 - 10.1371/journal.pgen.1003173

DO - 10.1371/journal.pgen.1003173

M3 - Article

VL - 9

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 3

M1 - e1003173

ER -