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

Gaudet, M. M.; Kuchenbaecker, K. B.; Vijai, J.; Klein, R. J.; Kirchhoff, T.; McGuffog, L.; Barrowdale, D.; Dunning, A. M.; Lee, A.; Dennis, J.; Healey, S.; Dicks, E.; Soucy, P.; Sinilnikova, O. M.; Pankratz, V. S.; Wang, X.; Eldridge, R. C.; Tessier, D. C.; Vincent, D.; Bacot, F.; Hogervorst, F. B. L.; Peock, S.; Stoppa-Lyonnet, D.; Coulet, F.; Colas, C.; Soubrier, F.; Peterlongo, P.; Schmutzler, R. K.; Nathanson, K. L.; Piedmonte, M.; Singer, C. F.; Thomassen, M.; Sokolowska, J.; Bronner, M.; Hansen, T. V. O.; Neuhausen, S. L.; Blanco, I.; Greene, M. H.; Garber, J.; Weitzel, J. N.; Andrulis, I. L.; Goldgar, D. E.; D'Andrea, E.; Caldes, T.; Nevanlinna, H.; Osorio, A.; van Rensburg, E. J.; Arason, A.; Rennert, G.; van den Ouweland, A. M. W.; van der Hout, A. H.; Kets, C. M.; Aalfs, C. M.; Wijnen, J. T.; Ausems, M. G. E. M.; Frost, D.; Ellis, S.; Fineberg, E.; Platte, R.; Evans, D. G.; Jacobs, C.; Adlard, J.; Tischkowitz, M.; Porteous, M. E.; Damiola, F.; Golmard, L.; Barjhoux, L.; Longy, M.; Belotti, M.; Ferrer, S. F.; Mazoyer, S.; Spurdle, A. B.; Manoukian, S.; Barile, M.; Genuardi, M.; Arnold, N.; Meindl, A.; Sutter, C.; Wappenschmidt, B.; Domchek, S. M.; Pfeiler, G.; Friedman, E.; Jensen, U. B.; Robson, M.; Shah, S.; Lazaro, C.; Mai, P. L.; Benitez, J.; Southey, M. C.; Schmidt, M. K.; Fasching, P. A.; Peto, J.; Humphreys, M. K.; Wang, Q.; Michailidou, K.; Sawyer, E. J.; Burwinkel, B.; Guénel, P.; Bojesen, S. E.; Milne, R. L.; Brenner, H.; Lochmann, M.; Brauch, H.; Ko, Y-D.; Baisch, C.; Fischer, H-P.; Bruening, T.; Pesch, B.; Rabstein, S.; Spickenheuer, A.; Aittomäki, K.; Dörk, T.; Margolin, S.; Mannermaa, A.; Lambrechts, D.; Chang-Claude, J.; Radice, P.; Giles, G. G.; Haiman, C. A.; Winqvist, R.; Devillee, P.; García-Closas, M.; Schoof, N.; Hooning, M. J.; Cox, A.; Pharoah, P. D. P.; Jakubowska, A.; Orr, N.; González-Neira, A.; Pita, G.; Alonso, M. R.; Hall, P.; Couch, F. J.; Simard, J.; Altshuler, D.; Easton, D. F.; Chenevix-Trench, G.; Antoniou, A. C.; Offit, K.; Rookus, M. A.; van Leeuwen, F. E.; Verhoef, S.; de Lange, J. L.; Collée, J. M.; Seynaeve, C.; van Deurzen, C. H. M.; van Asperen, C. J.; Tollenaar, R. A.; Devilee, P.; van Cronenburg, T. C. T. E. F.; Mensenkamp, A. R.; van der Luijt, R. B.; 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.; Mourits, M. J.; de Bock, G. H.; Vasen, H. F.; Miedzybrodzka, Z.; Gregory, H.; Morrison, P.; Jeffers, L.; Cole, T.; Ong, K-R.; Hoffman, J.; Donaldson, A.; James, M.; Paterson, J.; Taylor, A.; Murray, A.; Rogers, M. T.; McCann, E.; Kennedy, M. J.; 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.; Langman, C.; Brady, A.; Dorkins, H.; Melville, A.; Randhawa, K.; Barwell, 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, R. A.; 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.; Verny-Pierre, C.; Giraud, S.; Léone, M.; Gauthier-Villars, M.; Buecher, B.; Houdayer, C.; Moncoutier, V.; Tirapo, C.; de Pauw, A.; Bressac-de-Paillerets, B.; Caron, O.; Bignon, Y-J.; 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, J-P.; Fournier, J.; Révillion, F.; Vennin, P.; Adenis, C.; Rouleau, E.; Lidereau, R.; Demange, L.; Nogues, C.; Muller, D.; Fricker, J-P.; Barouk-Simonet, E.; Bonnet, F.; Bubien, V.; Sevenet, N.; Toulas, C.; Guimbaud, R.; Gladieff, L.; Feillel, V.; Dreyfus, H.; Rebischung, C.; Peysselon, M.; Coron, F.; Faivre, L.; Prieur, F.; Lebrun, M.; Kientz, C.; Frénay, M.; Vénat-Bouvet, L.; Delnatte, C.; Mortemousque, I.; Lynch, H. T.; Snyder, C. L.

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

journal contribution

posted on 2016-04-14, 09:22 authored by M. M. Gaudet, K. B. Kuchenbaecker, J. Vijai, R. J. Klein, T. Kirchhoff, L. McGuffog, D. Barrowdale, A. M. Dunning, A. Lee, J. Dennis, S. Healey, E. Dicks, P. Soucy, O. M. Sinilnikova, V. S. Pankratz, X. Wang, R. C. Eldridge, D. C. Tessier, D. Vincent, F. Bacot, F. B. L. Hogervorst, S. Peock, D. Stoppa-Lyonnet, F. Coulet, C. Colas, F. Soubrier, P. Peterlongo, R. K. Schmutzler, K. L. Nathanson, M. Piedmonte, C. F. Singer, M. Thomassen, J. Sokolowska, M. Bronner, T. V. O. Hansen, S. L. Neuhausen, I. Blanco, M. H. Greene, J. Garber, J. N. Weitzel, I. L. Andrulis, D. E. Goldgar, E. D'Andrea, T. Caldes, H. Nevanlinna, A. Osorio, E. J. van Rensburg, A. Arason, G. Rennert, A. M. W. van den Ouweland, A. H. van der Hout, C. M. Kets, C. M. Aalfs, J. T. Wijnen, M. G. E. M. Ausems, D. Frost, S. Ellis, E. Fineberg, R. Platte, D. G. Evans, C. Jacobs, J. Adlard, M. Tischkowitz, M. E. Porteous, F. Damiola, L. Golmard, L. Barjhoux, M. Longy, M. Belotti, S. F. Ferrer, S. Mazoyer, A. B. Spurdle, S. Manoukian, M. Barile, M. Genuardi, N. Arnold, A. Meindl, C. Sutter, B. Wappenschmidt, S. M. Domchek, G. Pfeiler, E. Friedman, U. B. Jensen, M. Robson, S. Shah, C. Lazaro, P. L. Mai, J. Benitez, M. C. Southey, M. K. Schmidt, P. A. Fasching, J. Peto, M. K. Humphreys, Q. Wang, K. Michailidou, E. J. Sawyer, B. Burwinkel, P. Guénel, S. E. Bojesen, R. L. Milne, H. Brenner, M. Lochmann, H. Brauch, Y-D. Ko, C. Baisch, H-P. Fischer, T. Bruening, B. Pesch, S. Rabstein, A. Spickenheuer, K. Aittomäki, T. Dörk, S. Margolin, A. Mannermaa, D. Lambrechts, J. Chang-Claude, P. Radice, G. G. Giles, C. A. Haiman, R. Winqvist, P. Devillee, M. García-Closas, N. Schoof, M. J. Hooning, A. Cox, P. D. P. Pharoah, A. Jakubowska, N. Orr, A. González-Neira, G. Pita, M. R. Alonso, P. Hall, F. J. Couch, J. Simard, D. Altshuler, D. F. Easton, G. Chenevix-Trench, A. C. Antoniou, K. Offit, M. A. Rookus, F. E. van Leeuwen, S. Verhoef, J. L. de Lange, J. M. Collée, C. Seynaeve, C. H. M. van Deurzen, C. J. van Asperen, R. A. Tollenaar, P. Devilee, T. C. T. E. F. van Cronenburg, A. R. Mensenkamp, R. B. van der Luijt, 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, M. J. Mourits, G. H. de Bock, H. F. Vasen, Z. Miedzybrodzka, H. Gregory, P. Morrison, L. Jeffers, T. Cole, K-R. Ong, J. Hoffman, A. Donaldson, M. James, J. Paterson, A. Taylor, A. Murray, M. T. Rogers, E. McCann, M. J. Kennedy, D. Barton, M. Porteous, S. Drummond, C. Brewer, E. Kivuva, A. Searle, S. Goodman, K. Hill, R. Davidson, V. Murday, N. Bradshaw, L. Snadden, M. Longmuir, C. Watt, S. Gibson, E. Haque, E. Tobias, A. Duncan, L. Izatt, C. Langman, A. Brady, H. Dorkins, A. Melville, K. Randhawa, J. Barwell, G. Serra-Feliu, I. Ellis, C. Houghton, F. Lalloo, J. Taylor, L. Side, A. Male, C. Berlin, J. Eason, R. Collier, F. Douglas, O. Claber, I. Jobson, L. Walker, D. McLeod, D. Halliday, S. Durell, B. Stayner, R. A. Eeles, S. Shanley, N. Rahman, R. Houlston, E. Bancroft, E. Page, A. Ardern-Jones, K. Kohut, J. Wiggins, E. Castro, E. Killick, S. Martin, G. Rea, A. Kulkarni, J. Cook, O. Quarrell, C. Bardsley, S. Hodgson, S. Goff, G. Brice, L. Winchester, C. Eddy, V. Tripathi, V. Attard, A. Lehmann, D. Eccles, A. Lucassen, G. Crawford, D. McBride, S. Smalley, O. Sinilnikova, C. Verny-Pierre, S. Giraud, M. Léone, M. Gauthier-Villars, B. Buecher, C. Houdayer, V. Moncoutier, C. Tirapo, A. de Pauw, B. Bressac-de-Paillerets, O. Caron, Y-J. Bignon, N. Uhrhammer, C. Lasset, V. Bonadona, S. Handallou, A. Hardouin, P. Berthet, H. Sobol, V. Bourdon, T. Noguchi, A. Remenieras, F. Eisinger, I. Coupier, P. Pujol, J-P. Peyrat, J. Fournier, F. Révillion, P. Vennin, C. Adenis, E. Rouleau, R. Lidereau, L. Demange, C. Nogues, D. Muller, J-P. Fricker, E. Barouk-Simonet, F. Bonnet, V. Bubien, N. Sevenet, C. Toulas, R. Guimbaud, L. Gladieff, V. Feillel, H. Dreyfus, C. Rebischung, M. Peysselon, F. Coron, L. Faivre, F. Prieur, M. Lebrun, C. Kientz, M. Frénay, L. Vénat-Bouvet, C. Delnatte, I. Mortemousque, H. T. Lynch, C. L. Snyder

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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PLoS Genetics, 2013, 9 (3), e1003173

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/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

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PLoS Genetics

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Public Library of Science

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1553-7390

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1553-7404

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2012-10-30

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2016-04-14

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https://doi.org/10.1371/journal.pgen.1003173

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http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003173

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en

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https://leicester.figshare.com/account/articles/10147805

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Breast cancer Genome-wide association studies Mutation Variant genotypes Genetic loci Consortia Mutation detection Genotyping

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

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