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Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

ABSTRACT: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

SUBMITTER: Ramus SJ

PROVIDER: S-EPMC3458423 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

Ramus Susan J SJ Antoniou Antonis C AC Kuchenbaecker Karoline B KB Soucy Penny P Beesley Jonathan J Chen Xiaoqing X McGuffog Lesley L Sinilnikova Olga M OM Healey Sue S Barrowdale Daniel D Lee Andrew A Thomassen Mads M Gerdes Anne-Marie AM Kruse Torben A TA Jensen Uffe Birk UB Skytte Anne-Bine AB Caligo Maria A MA Liljegren Annelie A Lindblom Annika A Olsson Håkan H Kristoffersson Ulf U Stenmark-Askmalm Marie M Melin Beatrice B Domchek Susan M SM Nathanson Katherine L KL Rebbeck Timothy R TR Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Złowocka Elżbieta E Gronwald Jacek J Huzarski Tomasz T Byrski Tomasz T Cybulski Cezary C Toloczko-Grabarek Aleksandra A Osorio Ana A Benitez Javier J Duran Mercedes M Tejada Maria-Isabel MI Hamann Ute U Rookus Matti M van Leeuwen Flora E FE Aalfs Cora M CM Meijers-Heijboer Hanne E J HE van Asperen Christi J CJ van Roozendaal K E P KE Hoogerbrugge Nicoline N Collée J Margriet JM Kriege Mieke M van der Luijt Rob B RB Peock Susan S Frost Debra D Ellis Steve D SD Platte Radka R Fineberg Elena E Evans D Gareth DG Lalloo Fiona F Jacobs Chris C Eeles Ros R Adlard Julian J Davidson Rosemarie R Eccles Diana D Cole Trevor T Cook Jackie J Paterson Joan J Douglas Fiona F Brewer Carole C Hodgson Shirley S Morrison Patrick J PJ Walker Lisa L Porteous Mary E ME Kennedy M John MJ Pathak Harsh H Godwin Andrew K AK Stoppa-Lyonnet Dominique D Caux-Moncoutier Virginie V de Pauw Antoine A Gauthier-Villars Marion M Mazoyer Sylvie S Léoné Mélanie M Calender Alain A Lasset Christine C Bonadona Valérie V Hardouin Agnès A Berthet Pascaline P Bignon Yves-Jean YJ Uhrhammer Nancy N Faivre Laurence L Loustalot Catherine C Buys Saundra S Daly Mary M Miron Alex A Terry Mary Beth MB Chung Wendy K WK John Esther M EM Southey Melissa M Goldgar David D Singer Christian F CF Tea Muy-Kheng MK Pfeiler Georg G Fink-Retter Anneliese A Hansen Thomas v O Tv Ejlertsen Bent B Johannsson Oskar Th OT Offit Kenneth K Kirchhoff Tomas T Gaudet Mia M MM Vijai Joseph J Robson Mark M Piedmonte Marion M Phillips Kelly-Anne KA Van Le Linda L Hoffman James S JS Ewart Toland Amanda A Montagna Marco M Tognazzo Silvia S Imyanitov Evgeny E Issacs Claudine C Janavicius Ramunas R Lazaro Conxi C Blanco Iganacio I Tornero Eva E Navarro Matilde M Moysich Kirsten B KB Karlan Beth Y BY Gross Jenny J Olah Edith E Vaszko Tibor T Teo Soo-Hwang SH Ganz Patricia A PA Beattie Mary S MS Dorfling Cecelia M CM van Rensburg Elizabeth J EJ Diez Orland O Kwong Ava A Schmutzler Rita K RK Wappenschmidt Barbara B Engel Christoph C Meindl Alfons A Ditsch Nina N Arnold Norbert N Heidemann Simone S Niederacher Dieter D Preisler-Adams Sabine S Gadzicki Dorotehea D Varon-Mateeva Raymonda R Deissler Helmut H Gehrig Andrea A Sutter Christian C Kast Karin K Fiebig Britta B Schäfer Dieter D Caldes Trinidad T de la Hoya Miguel M Nevanlinna Heli H Aittomäki Kristiina K Plante Marie M Spurdle Amanda B AB Neuhausen Susan L SL Ding Yuan Chun YC Wang Xianshu X Lindor Noralane N Fredericksen Zachary Z Pankratz V Shane VS Peterlongo Paolo P Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Bonanni Bernardo B Bernard Loris L Dolcetti Riccardo R Papi Laura L Ottini Laura L Radice Paolo P Greene Mark H MH Mai Phuong L PL Andrulis Irene L IL Glendon Gord G Ozcelik Hilmi H Pharoah Paul D P PD Gayther Simon A SA Simard Jacques J Easton Douglas F DF Couch Fergus J FJ Chenevix-Trench Georgia G

Human mutation 20120214 4

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were ge ...[more]

PMID: 22253144

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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:BackgroundGenome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.MethodsWe constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.ResultsThe PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.ConclusionsBC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

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.

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Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

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Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers.

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