Dataset Information

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

ABSTRACT: The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (?) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

SUBMITTER: Gaudet MM

PROVIDER: S-EPMC2965747 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Gaudet Mia M MM Kirchhoff Tomas T Green Todd T Vijai Joseph J Korn Joshua M JM Guiducci Candace C Segrè Ayellet V AV McGee Kate K McGuffog Lesley L Kartsonaki Christiana C Morrison Jonathan J Healey Sue S Sinilnikova Olga M OM Stoppa-Lyonnet Dominique D Mazoyer Sylvie S Gauthier-Villars Marion M Sobol Hagay H Longy Michel M Frenay Marc M GEMO Study Collaborators Hogervorst Frans B L FB Rookus Matti A MA Collée J Margriet JM Hoogerbrugge Nicoline N van Roozendaal Kees E P KE Piedmonte Marion M Rubinstein Wendy W Nerenstone Stacy S Van Le Linda L Blank Stephanie V SV Caldés Trinidad T de la Hoya Miguel M Nevanlinna Heli H Aittomäki Kristiina K Lazaro Conxi C Blanco Ignacio I Arason Adalgeir A Johannsson Oskar T OT Barkardottir Rosa B RB Devilee Peter P Olopade Olofunmilayo I OI Neuhausen Susan L SL Wang Xianshu X Fredericksen Zachary S ZS Peterlongo Paolo P Manoukian Siranoush S Barile Monica M Viel Alessandra A Radice Paolo P Phelan Catherine M CM Narod Steven S Rennert Gad G Lejbkowicz Flavio F Flugelman Anath A Andrulis Irene L IL Glendon Gord G Ozcelik Hilmi H Toland Amanda E AE Montagna Marco M D'Andrea Emma E Friedman Eitan E Laitman Yael Y Borg Ake A Beattie Mary M Ramus Susan J SJ Domchek Susan M SM Nathanson Katherine L KL Rebbeck Tim T Spurdle Amanda B AB Chen Xiaoqing X Holland Helene H John Esther M EM Hopper John L JL Buys Saundra S SS Daly Mary B MB Southey Melissa C MC Terry Mary Beth MB Tung Nadine N Overeem Hansen Thomas V TV Nielsen Finn C FC Greene Mark H MH Mai Phuong L PL Osorio Ana A Durán Mercedes M Andres Raquel R Benítez Javier J Weitzel Jeffrey N JN Garber Judy J Hamann Ute U Peock Susan S Cook Margaret M Oliver Clare C Frost Debra D Platte Radka R Evans D Gareth DG Lalloo Fiona F Eeles Ros R Izatt Louise L Walker Lisa L Eason Jacqueline J Barwell Julian J Godwin Andrew K AK Schmutzler Rita K RK Wappenschmidt Barbara B Engert Stefanie S Arnold Norbert N Gadzicki Dorothea D Dean Michael M Gold Bert B Klein Robert J RJ Couch Fergus J FJ Chenevix-Trench Georgia G Easton Douglas F DF Daly Mark J MJ Antoniou Antonis C AC Altshuler David M DM Offit Kenneth K

PLoS genetics 20101028 10

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were eva ...[more]

PMID: 21060860

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Project description:BACKGROUND: Breast cancer is the most common type of cancer and the second leading cause of cancer-death among women in Poland. The known high-risk mutations account for 25% of familial aggregation cases and 5% of total breast cancer predisposition. Genome-wide association studies have identified a number of common low-penetrance genetic variants, but their contribution to disease risk differs between populations. METHODS: To verify selected associations with breast cancer susceptibility among Polish women, the replication study was performed, included 1424 women with breast cancer and 1788 healthy persons. Sixteen single-nucleotide polymorphisms (SNPs) were analyzed using TaqMan SNP Genotyping Assays. Allele frequency differences were tested using chi2-test implemented in PLINK v1.07 and Cochran-Armitage trend test was performed using R software. RESULTS: Significant differences (Bonferroni corrected p-valuecor ? 0.0197) in the frequency of alleles distribution between all cancer and control subjects were observed for four (rs2736098, rs13281615, rs1219648, rs2981582) out of 16 SNPs. The same result was obtained for group of patients without high-risk BRCA1/2 mutations. The rs1219648 (p-valuecor ? 6.73E-03) and rs2981582 (p-valuecor ? 6.48E-03) SNPs showed significant association with both familial and sporadic cancers. Additionally, rs2736098 (p-valuecor ? 0.0234) was associated with only sporadic cancers; also in group without carriers of high-risk mutation. All these associations revealed their significance also in Cochran-Armitage trend test. Opposite to other SNPs, rs2736098 was associated with a decreased risk of breast cancer. CONCLUSION: The association of four known susceptibility SNPs, representing three individual loci, with breast cancer risk in Polish women was confirmed. One of them (rs2736098) seems to be specific for the Polish population. Due to the population differences in allele frequencies, identification of general genetic risk factors requires sets of association studies conducted on different populations.

Project description:A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

Dataset Information

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Publications

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

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