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 language | English |
|---|---|
| Article number | e1003173 |
| Journal | PLoS Genetics |
| Volume | 9 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Jan 2013 |
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: PLoS Genetics, Vol. 9, No. 3, e1003173, 01.01.2013.
Research output: Contribution to journal › Article › peer-review
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, M. 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, M. 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 - van Leeuwen, F. E.
AU - Verhoef, S.
AU - de Lange, J. L.
AU - Collée, J. M.
AU - Seynaeve, C.
AU - van Deurzen, C. H.M.
AU - van Asperen, C. J.
AU - Tollenaar, R. A.
AU - Devilee, P.
AU - van Cronenburg, T. C.T.E.F.
AU - Mensenkamp, A. R.
AU - van der Luijt, R. B.
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 - Mourits, M. J.
AU - de Bock, G. H.
AU - Vasen, H. F.
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 - 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 - Langman, Caroline
AU - Brady, Angela
AU - Dorkins, Huw
AU - Melville, Athalie
AU - Randhawa, Kashmir
AU - Barwell, 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 - Douglas, Fiona
AU - Claber, Oonagh
AU - Collier, Rebecca
AU - Jobson, Irene
AU - Walker, Lisa
AU - McLeod, Diane
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 - Verny-Pierre, Carole
AU - Giraud, Sophie
AU - Léone, Mélanie
AU - Gauthier-Villars, Marion
AU - Buecher, Bruno
AU - Houdayer, Claude
AU - Moncoutier, Virginie
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 - 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 - Demange, Liliane
AU - Nogues, Catherine
AU - Muller, Danièle
AU - Fricker, Jean Pierre
AU - Barouk-Simonet, Emmanuelle
AU - Bonnet, Françoise
AU - Bubien, Virginie
AU - Sevenet, Nicolas
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 - Frénay, Marc
AU - Vénat-Bouvet, Laurence
AU - Delnatte, Capucine
AU - Mortemousque, Isabelle
AU - Lynch, Henry T.
AU - Snyder, Carrie L.
PY - 2013/1/1
Y1 - 2013/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=84875733563&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1003173
DO - 10.1371/journal.pgen.1003173
M3 - Article
C2 - 23544012
AN - SCOPUS:84875733563
SN - 1553-7390
VL - 9
JO - PLoS Genetics
JF - PLoS Genetics
IS - 3
M1 - e1003173
ER -