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. 2010 Dec 1;70(23):9742-54.
doi: 10.1158/0008-5472.CAN-10-1907. Epub 2010 Nov 30.

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

Antonis C Antoniou  1 , Jonathan Beesley, Lesley McGuffog, Olga M Sinilnikova, Sue Healey, Susan L Neuhausen, Yuan Chun Ding, Timothy R Rebbeck, Jeffrey N Weitzel, Henry T Lynch, Claudine Isaacs, Patricia A Ganz, Gail Tomlinson, Olufunmilayo I Olopade, Fergus J Couch, Xianshu Wang, Noralane M Lindor, Vernon S Pankratz, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Alessandra Viel, Anna Allavena, Valentina Dall'Olio, Paolo Peterlongo, Csilla I Szabo, Michal Zikan, Kathleen Claes, Bruce Poppe, Lenka Foretova, Phuong L Mai, Mark H Greene, Gad Rennert, Flavio Lejbkowicz, Gord Glendon, Hilmi Ozcelik, Irene L Andrulis; Ontario Cancer Genetics Network; Mads Thomassen, Anne-Marie Gerdes, Lone Sunde, Dorthe Cruger, Uffe Birk Jensen, Maria Caligo, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Maya Dubrovsky, Shimrit Cohen, Ake Borg, Helena Jernström, Annika Lindblom, Johanna Rantala, Marie Stenmark-Askmalm, Beatrice Melin; SWE-BRCA; Kate Nathanson, Susan Domchek, Ania Jakubowska, Jan Lubinski, Tomasz Huzarski, Ana Osorio, Adriana Lasa, Mercedes Durán, Maria-Isabel Tejada, Javier Godino, Javier Benitez, Ute Hamann, Mieke Kriege, Nicoline Hoogerbrugge, Rob B van der Luijt, Christi J van Asperen, Peter Devilee, E J Meijers-Heijboer, Marinus J Blok, Cora M Aalfs, Frans Hogervorst, Matti Rookus; HEBON; Margaret Cook, Clare Oliver, Debra Frost, Don Conroy, D Gareth Evans, Fiona Lalloo, Gabriella Pichert, Rosemarie Davidson, Trevor Cole, Jackie Cook, Joan Paterson, Shirley Hodgson, Patrick J Morrison, Mary E Porteous, Lisa Walker, M John Kennedy, Huw Dorkins, Susan Peock; EMBRACE; Andrew K Godwin, Dominique Stoppa-Lyonnet, Antoine de Pauw, Sylvie Mazoyer, Valérie Bonadona, Christine Lasset, Hélène Dreyfus, Dominique Leroux, Agnès Hardouin, Pascaline Berthet, Laurence Faivre; GEMO; Catherine Loustalot, Tetsuro Noguchi, Hagay Sobol, Etienne Rouleau, Catherine Nogues, Marc Frénay, Laurence Vénat-Bouvet; GEMO; John L Hopper, Mary B Daly, Mary B Terry, Esther M John, Saundra S Buys, Yosuf Yassin, Alexander Miron, David Goldgar; Breast Cancer Family Registry; Christian F Singer, Anne Catharina Dressler, Daphne Gschwantler-Kaulich, Georg Pfeiler, Thomas V O Hansen, Lars Jønson, Bjarni A Agnarsson, Tomas Kirchhoff, Kenneth Offit, Vincent Devlin, Ana Dutra-Clarke, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Peter E Schwartz, Stephanie V Blank, Amanda Ewart Toland, Marco Montagna, Cinzia Casella, Evgeny Imyanitov, Laima Tihomirova, Ignacio Blanco, Conxi Lazaro, Susan J Ramus, Lara Sucheston, Beth Y Karlan, Jenny Gross, Rita Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Magdalena Lochmann, Norbert Arnold, Simone Heidemann, Raymonda Varon-Mateeva, Dieter Niederacher, Christian Sutter, Helmut Deissler, Dorothea Gadzicki, Sabine Preisler-Adams, Karin Kast, Ines Schönbuchner, Trinidad Caldes, Miguel de la Hoya, Kristiina Aittomäki, Heli Nevanlinna, Jacques Simard, Amanda B Spurdle, Helene Holland, Xiaoqing Chen; kConFab; Radka Platte, Georgia Chenevix-Trench, Douglas F Easton; CIMBA
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Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

Antonis C Antoniou et al. Cancer Res. .

Abstract

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

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Figures

Figure 1
Figure 1
Study specific per-allele HR estimates for BRCA1 mutation carriers for SNPs rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 in the 5p12. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% confidence intervals.
Figure 2
Figure 2
Study specific per-allele HR estimates for BRCA2 mutation carriers for SNPs rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 in the 5p12. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% confidence intervals.
Figure 3
Figure 3
A. Cumulative distribution function of the combined hazard ratio for breast cancer risk for BRCA2 mutation carriers at SNPs rs2981582 in FGFR2, rs3803662 in TOX3/TNRC9, rs889312 in MAP3K1, rs3817198 in LSP1, rs13387042 in 2q35 region, rs4973768 in SLC4A7/NEK10 and rs10941679 in the 5p12 region (see methods for definition of combined HR). B. Predicted cumulative risk of developing breast cancer by age 80 for BRCA2 mutation carriers by the combined HR at the above SNPs.
Figure 4
Figure 4
Age specific cumulative breast cancer risks for BRCA2 mutation carriers by percentiles of the combined genotype distribution at SNPs rs2981582 in FGFR2, rs3803662 in TOX3/TNRC9, rs889312 in MAP3K1, rs3817198 in LSP1, rs13387042 in 2q35 region, rs4973768 in SLC4A7/NEK10 and rs10941679 in the 5p12 region.
See this image and copyright information in PMC

References

    1. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117–30. - PMC - PubMed
    1. Begg CB, Haile RW, Borg A, et al. Variation of breast cancer risk among BRCA1/2 carriers. JAMA. 2008;299:194–201. - PMC - PubMed
    1. Simchoni S, Friedman E, Kaufman B, et al. Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc Natl Acad Sci U S A. 2006;103:3770–4. - PMC - PubMed
    1. Antoniou AC, Cunningham AP, Peto J, et al. The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions. Br J Cancer. 2008;98:1457–66. - PMC - PubMed
    1. Chenevix-Trench G, Milne RL, Antoniou AC, Couch FJ, Easton DF, Goldgar DE. An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) Breast Cancer Res. 2007;9:104. - PMC - PubMed

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