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; Cuningham, Kathleen; Peterlongo, Paolo; Schmutzler, Rita K.; Nathanson, Katherine L.; Piedmonte, Marion; Singer, Christian F.; Thomassen, Mads; Lunenfeld, Samuel; Hansen, Thomas V.O.; Neuhausen, Susan L.; Blanco, Ignacio; Greene, Mark H.; Garber, Judy; Weitzel, Jeffrey N.; Andrulis, Irene L.; Goldgar, David E.; D’Andrea, Emma; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Jansen van Rensburg, Elizabeth; 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; Guenel, Pascal; Bojesen, Stig E.; Milne, Roger L.; Brenner, Hermann; Lochmann, Magdalena; Fischer-Bosch, Margarete; Aittomaki, Kristiina; Dork, Thilo; Margolin, Sara; Mannermaa, Arto; Lambrechts, Diether; Chang-Claude, Jenny; Radice, Paolo; Giles, Graham G.; Haiman, Christopher A.; Winqvist, Robert; Devilee, Peter; Garcıa-Closas, Montserrat; Schoof, Nils; Hooning, Maartje J.; Cox, Angela; Pharoah, Paul D.P.; Jakubowska, Anna; Orr, Nick; Gonzalez-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

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; Cuningham, Kathleen; Peterlongo, Paolo; Schmutzler, Rita K.; Nathanson, Katherine L.; Piedmonte, Marion; Singer, Christian F.; Thomassen, Mads; Lunenfeld, Samuel; Hansen, Thomas V.O.; Neuhausen, Susan L.; Blanco, Ignacio; Greene, Mark H.; Garber, Judy; Weitzel, Jeffrey N.; Andrulis, Irene L.; Goldgar, David E.; D’Andrea, Emma; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Jansen van Rensburg, Elizabeth; 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; Guenel, Pascal; Bojesen, Stig E.; Milne, Roger L.; Brenner, Hermann; Lochmann, Magdalena; Fischer-Bosch, Margarete; Aittomaki, Kristiina; Dork, Thilo; Margolin, Sara; Mannermaa, Arto; Lambrechts, Diether; Chang-Claude, Jenny; Radice, Paolo; Giles, Graham G.; Haiman, Christopher A.; Winqvist, Robert; Devilee, Peter; Garcıa-Closas, Montserrat; Schoof, Nils; Hooning, Maartje J.; Cox, Angela; Pharoah, Paul D.P.; Jakubowska, Anna; Orr, Nick; Gonzalez-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; Hunter, Kent W.

URI: http://hdl.handle.net/2263/21555

Date: 2013-03-27

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 = 3.9x10 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.

Description:

Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.

Conceived and designed the experiments: P Hall, FJ Couch, J Simard, D Altshuler, DF Easton, G Chenevix-Trench, AC Antoniou, K Offit. Performed the experiments: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ Klein, T Kirchhoff. Analyzed the data: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ Klein, L McGuffog, D Barrowdale, AM Dunning, J Simard, D Altshuler, DF Easton, AC Antoniou, K Offit. Contributed reagents/ materials/analysis tools: L McGuffog, D Barrowdale, AM Dunning, A Lee, J Dennis, S Healey, E Dicks, P Soucy, OM Sinilnikova, VS Pankratz, X Wang, RC Eldridge, DC Tessier, D Vincent, F Bacot, FBL Hogervorst, S Peock, D Stoppa-Lyonnet, P Peterlongo, RK Schmutzler, KL Nathanson, M Piedmonte, CF Singer, M Thomassen, TvO Hansen, SL Neuhausen, I Blanco, MH Greene, J Garber, JN Weitzel, IL Andrulis, DE Goldgar, E D’Andrea, T Caldes, H Nevanlinna, A Osorio, EJ van Rensburg, A Arason, G Rennert, AMW van den Ouweland, AH van der Hout, CM Kets, CM Aalfs, JT Wijnen, MGEM Ausems, D Frost, S Ellis, E Fineberg, R Platte, DG Evans, C Jacobs, J Adlard, M Tischkowitz, ME Porteous, F Damiola, L Golmard, L Barjhoux, M Longy, M Belotti, SF Ferrer, S Mazoyer, AB Spurdle, S Manoukian, M Barile, M Genuardi, N Arnold, A Meindl, C Sutter, B Wappenschmidt, SM Domchek, G Pfeiler, E Friedman, UB Jensen, M Robson, S Shah, C Lazaro, PL Mai, J Benitez, MC Southey, MK Schmidt, PA Fasching, J Peto, MK Humphreys, Q Wang, K Michailidou, EJ Sawyer, B Burwinkel, P Gue´nel, SE Bojesen, RL Milne, H Brenner, M Lochmann, K Aittoma¨ ki, T Do¨rk, S Margolin, A Mannermaa, D Lambrechts, J Chang-Claude, P Radice, GG Giles, CA Haiman, R Winqvist, P Devillee, M Garcı´a-Closas, N Schoof, MJ Hooning, A Cox, PDP Pharoah, A Jakubowska, N Orr, A Gonza´lez-Neira, G Pita, MR Alonso, P Hall, FJ Couch, DF Easton, G Chenevix-Trench, AC Antoniou, K Offit. Wrote the paper: MM Gaudet, KB Kuchenbaecker, J Vijai, RJ Klein, AC Antoniou, K Offit.

Figure S1 Cluster plots for SNPs (A.) rs9348512, (B.) rs619373, and (C.) rs184577.

Figure S2 Multidimensional scaling plots of the top two principal components of genomic ancestry of all eligible BRCA2 iCOGS samples plotted with the HapMap CEU, ASI, and YRI samples: (A.) samples from Finland and BRCA2 6174delT carriers highlighted, and (B.) samples, indicated in red, with .19% non- European ancestry were excluded.

Figure S3 Quantile–quantile plot comparing expected and observed distributions of P-values. Results displayed (A) for the complete sample, (B) after excluding samples from the GWAS discovery stage, and (C) for the complete sample and a set of SNPs from the iCOGS array that were selected independent from the results of the BRCA2 mutation carriers.

Figure S4 Manhattan plot of P-values by chromosomal position for 18,086 SNPs selected on the basis of a previously published genome-wide association study of BRCA2 mutation carriers. Breast cancer associations results based on 4,330 breast cancer cases and 3,881 unaffected BRCA2 carriers.

Figure S5 Forest plot of the country-specific, per-allele hazard ratios (HR) and 95% confidence intervals for the association between breast cancer and rs9348512 genotypes.

Figure S6 Forest plot of the country-specific, per-allele hazard ratios (HR) and 95% confidence intervals for the association with breast cancer for (A.) rs619373 and (B.) rs184577 genotypes.

Table S1 Quality control filtering steps for BRCA2 mutation carriers and SNPs on the COGs array.

Table S2 Description of breast cancer affected and unaffected BRCA2 carriers included in the final analysis of the COGs array SNPs.

Table S3 Breast cancer hazards ratios (HR) and 95% confidence intervals (CI) for all SNPs with P,1023 in a 500 Mb region around rs9348512 on 6p24 among BRCA2 mutation carriers.

Table S4 Associations with SNPs at 6p24, FGF13 and 2p22 and breast and ovarian cancer risk using a competing risk analysis model.

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