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Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

ABSTRACT: BACKGROUND:Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. METHODS:We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. RESULTS:The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10(-9)) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10(-4)). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. CONCLUSION:Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

SUBMITTER: Ramus SJ

PROVIDER: S-EPMC3107565 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

Ramus Susan J SJ Kartsonaki Christiana C Gayther Simon A SA Pharoah Paul D P PD Sinilnikova Olga M OM Beesley Jonathan J Chen Xiaoqing X McGuffog Lesley L Healey Sue S Couch Fergus J FJ Wang Xianshu X Fredericksen Zachary Z Peterlongo Paolo P Manoukian Siranoush S Peissel Bernard B Zaffaroni Daniela D Roversi Gaia G Barile Monica M Viel Alessandra A Allavena Anna A Ottini Laura L Papi Laura L Gismondi Viviana V Capra Fabio F Radice Paolo P Greene Mark H MH Mai Phuong L PL Andrulis Irene L IL Glendon Gord G Ozcelik Hilmi H Thomassen Mads M Gerdes Anne-Marie AM Kruse Torben A TA Cruger Dorthe D Jensen Uffe Birk UB Caligo Maria Adelaide MA Olsson Håkan H Kristoffersson Ulf U Lindblom Annika A Arver Brita B Karlsson Per P Stenmark Askmalm Marie M Borg Ake A Neuhausen Susan L SL Ding Yuan Chun YC Nathanson Katherine L KL Domchek Susan M SM Jakubowska Anna A Lubiński Jan J Huzarski Tomasz T Byrski Tomasz T Gronwald Jacek J Górski Bohdan B Cybulski Cezary C Dębniak Tadeusz T Osorio Ana A Durán Mercedes M Tejada Maria-Isabel MI Benítez Javier J Hamann Ute U Rookus Matti A MA Verhoef Senno S Tilanus-Linthorst Madeleine A MA Vreeswijk Maaike P MP Bodmer Danielle D Ausems Margreet G E M MG van Os Theo A TA Asperen Christi J CJ Blok Marinus J MJ Meijers-Heijboer Hanne E J HE Peock Susan S Cook Margaret M Oliver Clare C Frost Debra D Dunning Alison M AM Evans D Gareth DG Eeles Ros R Pichert Gabriella G Cole Trevor T Hodgson Shirley S Brewer Carole C Morrison Patrick J PJ Porteous Mary M Kennedy M John MJ Rogers Mark T MT Side Lucy E LE Donaldson Alan A Gregory Helen H Godwin Andrew A Stoppa-Lyonnet Dominique D Moncoutier Virginie V Castera Laurent L Mazoyer Sylvie S Barjhoux Laure L Bonadona Valérie V Leroux Dominique D Faivre Laurence L Lidereau Rosette R Nogues Catherine C Bignon Yves-Jean YJ Prieur Fabienne F Collonge-Rame Marie-Agnès MA Venat-Bouvet Laurence L Fert-Ferrer Sandra S Miron Alex A Buys Saundra S SS Hopper John L JL Daly Mary B MB John Esther M EM Terry Mary Beth MB Goldgar David D Hansen Thomas v O Tv Jønson Lars L Ejlertsen Bent B Agnarsson Bjarni A BA Offit Kenneth K Kirchhoff Tomas T Vijai Joseph J Dutra-Clarke Ana V C AV Przybylo Jennifer A JA Montagna Marco M Casella Cinzia C Imyanitov Evgeny N EN Janavicius Ramunas R Blanco Ignacio I Lázaro Conxi C Moysich Kirsten B KB Karlan Beth Y BY Gross Jenny J Beattie Mary S MS Schmutzler Rita R Wappenschmidt Barbara B Meindl Alfons A Ruehl Ina I Fiebig Britta B Sutter Christian C Arnold Norbert N Deissler Helmut H Varon-Mateeva Raymonda R Kast Karin K Niederacher Dieter D Gadzicki Dorothea D Caldes Trinidad T de la Hoya Miguel M Nevanlinna Heli H Aittomäki Kristiina K Simard Jacques J Soucy Penny P Spurdle Amanda B AB Holland Helene H Chenevix-Trench Georgia G Easton Douglas F DF Antoniou Antonis C AC

Journal of the National Cancer Institute 20101217 2

<h4>Background</h4>Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk o ...[more]

PMID: 21169536

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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:Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

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Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

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Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers.

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