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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.

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.

SUBMITTER: Antoniou AC

PROVIDER: S-EPMC2999830 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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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.

Antoniou Antonis C AC Beesley Jonathan J McGuffog Lesley L Sinilnikova Olga M OM Healey Sue S Neuhausen Susan L SL Ding Yuan Chun YC Rebbeck Timothy R TR Weitzel Jeffrey N JN Lynch Henry T HT Isaacs Claudine C Ganz Patricia A PA Tomlinson Gail G Olopade Olufunmilayo I OI Couch Fergus J FJ Wang Xianshu X Lindor Noralane M NM Pankratz Vernon S VS Radice Paolo P Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Barile Monica M Viel Alessandra A Allavena Anna A Dall'Olio Valentina V Peterlongo Paolo P Szabo Csilla I CI Zikan Michal M Claes Kathleen K Poppe Bruce B Foretova Lenka L Mai Phuong L PL Greene Mark H MH Rennert Gad G Lejbkowicz Flavio F Glendon Gord G Ozcelik Hilmi H Andrulis Irene L IL Thomassen Mads M Gerdes Anne-Marie AM Sunde Lone L Cruger Dorthe D Birk Jensen Uffe U Caligo Maria M Friedman Eitan E Kaufman Bella B Laitman Yael Y Milgrom Roni R Dubrovsky Maya M Cohen Shimrit S Borg Ake A Jernström Helena H Lindblom Annika A Rantala Johanna J Stenmark-Askmalm Marie M Melin Beatrice B Nathanson Kate K Domchek Susan S Jakubowska Ania A Lubinski Jan J Huzarski Tomasz T Osorio Ana A Lasa Adriana A Durán Mercedes M Tejada Maria-Isabel MI Godino Javier J Benitez Javier J Hamann Ute U Kriege Mieke M Hoogerbrugge Nicoline N van der Luijt Rob B RB van Asperen Christi J CJ Devilee Peter P Meijers-Heijboer E J EJ Blok Marinus J MJ Aalfs Cora M CM Hogervorst Frans F Rookus Matti M Cook Margaret M Oliver Clare C Frost Debra D Conroy Don D Evans D Gareth DG Lalloo Fiona F Pichert Gabriella G Davidson Rosemarie R Cole Trevor T Cook Jackie J Paterson Joan J Hodgson Shirley S Morrison Patrick J PJ Porteous Mary E ME Walker Lisa L Kennedy M John MJ Dorkins Huw H Peock Susan S Godwin Andrew K AK Stoppa-Lyonnet Dominique D de Pauw Antoine A Mazoyer Sylvie S Bonadona Valérie V Lasset Christine C Dreyfus Hélène H Leroux Dominique D Hardouin Agnès A Berthet Pascaline P Faivre Laurence L Loustalot Catherine C Noguchi Tetsuro T Sobol Hagay H Rouleau Etienne E Nogues Catherine C Frénay Marc M Vénat-Bouvet Laurence L 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 Dressler Anne Catharina AC Gschwantler-Kaulich Daphne D Pfeiler Georg G Hansen Thomas V O TV Jønson Lars L Agnarsson Bjarni A BA Kirchhoff Tomas T Offit Kenneth K Devlin Vincent V Dutra-Clarke Ana A 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 Ewart AE Montagna Marco M Casella Cinzia C Imyanitov Evgeny E Tihomirova Laima L Blanco Ignacio I Lazaro Conxi C Ramus Susan J SJ Sucheston Lara L Karlan Beth Y BY Gross Jenny J Schmutzler Rita R Wappenschmidt Barbara B Engel Christoph C Meindl Alfons A Lochmann Magdalena M Arnold Norbert N Heidemann Simone S Varon-Mateeva Raymonda R Niederacher Dieter D Sutter Christian C Deissler Helmut H Gadzicki Dorothea D Preisler-Adams Sabine S Kast Karin K Schönbuchner Ines I Caldes Trinidad T de la Hoya Miguel M Aittomäki Kristiina K Nevanlinna Heli H Simard Jacques J Spurdle Amanda B AB Holland Helene H Chen Xiaoqing X Platte Radka R Chenevix-Trench Georgia G Easton Douglas F DF

Cancer research 20101130 23

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 ...[more]

PMID: 21118973

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

Publications

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

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