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Multicenter Study
. 2009 Nov 15;18(22):4442-56.
doi: 10.1093/hmg/ddp372. Epub 2009 Aug 5.

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou  1 , Olga M Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer; Susan L Neuhausen, Yuan C Ding, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris Bernard, Paolo Radice, Csilla I Szabo, Lenka Foretova, Michal Zikan, Kathleen Claes, Mark H Greene, Phuong L Mai, Gad Rennert, Flavio Lejbkowicz, Irene L Andrulis, Hilmi Ozcelik, Gord Glendon; OCGN; Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M Domchek, Katherine L Nathanson, Ana Osorio, Ignacio Blanco, Adriana Lasa, Javier Benítez, Ute Hamann, Frans B L Hogervorst, Matti A Rookus, J Margriet Collee, Peter Devilee, Marjolijn J Ligtenberg, Rob B van der Luijt, Cora M Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E P van Roozendaal; HEBON; Susan Peock, Margaret Cook, Debra Frost, Clare Oliver, Radka Platte, D Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Rosemarie Davidson, Carol Chu, Diana Eccles, Trevor Cole, Shirley Hodgson; EMBRACE; Andrew K Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Mélanie Léoné, Brigitte Bressac-de Paillerets, Audrey Remenieras, Olivier Caron, Gilbert M Lenoir, Nicolas Sevenet, Michel Longy, Sandra Fert Ferrer, Fabienne Prieur; GEMO; David Goldgar, Alexander Miron, Esther M John, Saundra S Buys, Mary B Daly, John L Hopper, Mary Beth Terry, Yosuf Yassin; Breast Cancer Family Registry; Christian Singer, Daphne Gschwantler-Kaulich, Christine Staudigl, Thomas v O Hansen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Prodipto Pal, Kristi Kosarin, Kenneth Offit, Marion Piedmonte, Gustavo C Rodriguez, Katie Wakeley, John F Boggess, Jack Basil, Peter E Schwartz, Stephanie V Blank, Amanda E Toland, Marco Montagna, Cinzia Casella, Evgeny N Imyanitov, Anna Allavena, Rita K Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Britta Fiebig, Christian Suttner, Ines Schönbuchner, Dorothea Gadzicki, Trinidad Caldes, Miguel de la Hoya, Karen A Pooley, Douglas F Easton, Georgia Chenevix-Trench; CIMBA
Collaborators, Affiliations
Multicenter Study

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou et al. Hum Mol Genet. .

Abstract

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

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Figures

Figure 1.
Figure 1.
Study-specific per-allele HR estimates for SNP rs3817198 in LSP1. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% confidence intervals.
Figure 2.
Figure 2.
Study-specific HR estimates for SNP rs13387042 at 2q35 under the dominant model. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% confidence intervals.
Figure 3.
Figure 3.
Study-specific per-allele HR estimates for SNP rs13281615 at 8q24. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% confidence intervals.
See this image and copyright information in PMC

References

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