Dataset Information

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

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.

SUBMITTER: Antoniou AC

PROVIDER: S-EPMC2782243 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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

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

Human molecular genetics 20090805 22

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 ...[more]

PMID: 19656774

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Project description:INTRODUCTION:More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS:We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS:The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)?=?0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC?=?0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC?=?0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P <10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS:Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Dataset Information

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

Publications

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

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