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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

ABSTRACT: Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

SUBMITTER: Antoniou AC

PROVIDER: S-EPMC3652640 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Antoniou Antonis C AC Kartsonaki Christiana C Sinilnikova Olga M OM Soucy Penny P McGuffog Lesley L Healey Sue S Lee Andrew A Peterlongo Paolo P Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Cattaneo Elisa E Barile Monica M Pensotti Valeria V Pasini Barbara B Dolcetti Riccardo R Giannini Giuseppe G Putignano Anna Laura AL Varesco Liliana L Radice Paolo P Mai Phuong L PL Greene Mark H MH Andrulis Irene L IL Glendon Gord G Ozcelik Hilmi H Thomassen Mads M Gerdes Anne-Marie AM Kruse Torben A TA Birk Jensen Uffe U Crüger Dorthe G DG Caligo Maria A MA Laitman Yael Y Milgrom Roni R Kaufman Bella B Paluch-Shimon Shani S Friedman Eitan E Loman Niklas N Harbst Katja K Lindblom Annika A Arver Brita B Ehrencrona Hans H Melin Beatrice B Nathanson Katherine L KL Domchek Susan M SM Rebbeck Timothy T Jakubowska Ania A Lubinski Jan J Gronwald Jacek J Huzarski Tomasz T Byrski Tomasz T Cybulski Cezary C Gorski Bohdan B Osorio Ana A Ramón y Cajal Teresa T Fostira Florentia F Andrés Raquel R Benitez Javier J Hamann Ute U Hogervorst Frans B FB Rookus Matti A MA Hooning Maartje J MJ Nelen Marcel R MR van der Luijt Rob B RB van Os Theo A M TA van Asperen Christi J CJ Devilee Peter P Meijers-Heijboer Hanne E J HE Gómez Garcia Encarna B EB Peock Susan S Cook Margaret M Frost Debra D Platte Radka R Leyland Jean J Evans D Gareth DG Lalloo Fiona F Eeles Ros R Izatt Louise L Adlard Julian J Davidson Rosemarie R Eccles Diana D Ong Kai-ren KR Cook Jackie J Douglas Fiona F Paterson Joan J Kennedy M John MJ Miedzybrodzka Zosia Z Godwin Andrew A Stoppa-Lyonnet Dominique D Buecher Bruno B Belotti Muriel M Tirapo Carole C Mazoyer Sylvie S Barjhoux Laure L Lasset Christine C Leroux Dominique D Faivre Laurence L Bronner Myriam M Prieur Fabienne F Nogues Catherine C Rouleau Etienne E Pujol Pascal P Coupier Isabelle I Frénay Marc M Hopper John L JL Daly Mary B MB Terry Mary B MB John Esther M EM Buys Saundra S SS Yassin Yosuf Y Miron Alexander A Goldgar David D Singer Christian F CF Tea Muy-Kheng MK Pfeiler Georg G Dressler Anne Catharina AC Hansen Thomas v O Tv Jønson Lars L Ejlertsen Bent B Barkardottir Rosa Bjork RB Kirchhoff Tomas T Offit Kenneth K Piedmonte Marion M Rodriguez Gustavo G Small Laurie L Boggess John J Blank Stephanie S Basil Jack J Azodi Masoud M Toland Amanda Ewart AE Montagna Marco M Tognazzo Silvia S Agata Simona S Imyanitov Evgeny E Janavicius Ramunas R Lazaro Conxi C Blanco Ignacio I Pharoah Paul D P PD Sucheston Lara L Karlan Beth Y BY Walsh Christine S CS Olah Edith E Bozsik Aniko A Teo Soo-Hwang SH Seldon Joyce L JL Beattie Mary S MS van Rensburg Elizabeth J EJ Sluiter Michelle D MD Diez Orland O Schmutzler Rita K RK Wappenschmidt Barbara B Engel Christoph C Meindl Alfons A Ruehl Ina I Varon-Mateeva Raymonda R Kast Karin K Deissler Helmut H Niederacher Dieter D Arnold Norbert N Gadzicki Dorothea D Schönbuchner Ines I Caldes Trinidad T de la Hoya Miguel M Nevanlinna Heli H Aittomäki Kristiina K Dumont Martine M Chiquette Jocelyne J Tischkowitz Marc M Chen Xiaoqing X Beesley Jonathan J Spurdle Amanda B AB Neuhausen Susan L SL Chun Ding Yuan Y Fredericksen Zachary Z Wang Xianshu X Pankratz Vernon S VS Couch Fergus F Simard Jacques J Easton Douglas F DF Chenevix-Trench Georgia G

Human molecular genetics 20110518 16

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mu ...[more]

PMID: 21593217

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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.

Project description:INTRODUCTION:Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS:We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS:The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS:The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

Dataset Information

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

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