Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.
Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.
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DOI：
10.1371/journal.pgen.1001183
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发表时间：
2010-10-28
期刊：
影响因子：
4.5
通讯作者：
Offit K
中科院分区：
文献类型：
--
作者：
Gaudet MM;Kirchhoff T;Green T;Vijai J;Korn JM;Guiducci C;Segrè AV;McGee K;McGuffog L;Kartsonaki C;Morrison J;Healey S;Sinilnikova OM;Stoppa-Lyonnet D;Mazoyer S;Gauthier-Villars M;Sobol H;Longy M;Frenay M;GEMO Study Collaborators;Hogervorst FB;Rookus MA;Collée JM;Hoogerbrugge N;van Roozendaal KE;HEBON Study Collaborators;Piedmonte M;Rubinstein W;Nerenstone S;Van Le L;Blank SV;Caldés T;de la Hoya M;Nevanlinna H;Aittomäki K;Lazaro C;Blanco I;Arason A;Johannsson OT;Barkardottir RB;Devilee P;Olopade OI;Neuhausen SL;Wang X;Fredericksen ZS;Peterlongo P;Manoukian S;Barile M;Viel A;Radice P;Phelan CM;Narod S;Rennert G;Lejbkowicz F;Flugelman A;Andrulis IL;Glendon G;Ozcelik H;OCGN;Toland AE;Montagna M;D'Andrea E;Friedman E;Laitman Y;Borg A;Beattie M;Ramus SJ;Domchek SM;Nathanson KL;Rebbeck T;Spurdle AB;Chen X;Holland H;kConFab;John EM;Hopper JL;Buys SS;Daly MB;Southey MC;Terry MB;Tung N;Overeem Hansen TV;Nielsen FC;Greene MH;Mai PL;Osorio A;Durán M;Andres R;Benítez J;Weitzel JN;Garber J;Hamann U;EMBRACE;Peock S;Cook M;Oliver C;Frost D;Platte R;Evans DG;Lalloo F;Eeles R;Izatt L;Walker L;Eason J;Barwell J;Godwin AK;Schmutzler RK;Wappenschmidt B;Engert S;Arnold N;Gadzicki D;Dean M;Gold B;Klein RJ;Couch FJ;Chenevix-Trench G;Easton DF;Daly MJ;Antoniou AC;Altshuler DM;Offit K
关于与BRCA 2遗传突变相关的癌症风险的相当大的不确定性是由于未知因素。为了研究常见的遗传变异是否会改变BRCA 2突变携带者的遗传易感性，我们在BRCA 2突变携带者中进行了两阶段的全基因组关联研究。在第1阶段，使用Affyandroid 6.0平台，在899名受影响的年轻人（<40岁）和804名未受影响的欧洲血统携带者中获得了592，163个过滤的SNP基因型。使用基于生存率的评分测试评估相关性，该测试调整了家族相关性，并按研究国家和BRCA 2 * 6174 delT突变状态分层。基因组膨胀因子（λ）为1.011。第1阶段关联分析显示了与乳腺癌风险相关的多种变异：3个SNP的p值<10−5，39个SNP的p值<10−4。这些变异包括几个先前与散发性乳腺癌风险相关的基因和20号染色体（rs311499）和10号染色体（rs 16917302）上的两个新基因座。10号染色体的基因座位于ZNF 365，其中含有另一种变异，最近在一项独立的乳腺癌病例研究中发现这种变异与乳腺癌有关。在第2阶段，在1,264例病例和1,222例对照中对来自第1阶段的前85个位点进行基因分型。使用回顾性似然法合并并估计第1和第2阶段的风险比（HR）和95%置信区间（CI），并按居住国和最常见的突变BRCA 2 * 6174 delT分层。新基因座rs 16917302和rs311499的次要等位基因的组合每个等位基因HR分别为0.75（95% CI 0.66-0.86）和0.72（95% CI 0.61-0.85）。FGFR 2 rs 2981575与乳腺癌风险的相关性最强（每个等位基因HR = 1.28，95% CI 1.18-1.39）。 这些结果表明，迄今为止通过不可知方法鉴定的修饰BRCA 2突变的SNP仅限于也修饰散发性BRCA 2野生型乳腺癌风险的变体。与BRCA 2突变相关的乳腺癌风险差异很大。为了确定常见的遗传变异是否会改变BRCA 2突变的遗传率，我们使用两阶段方法在BRCA 2突变的女性中进行了第一次全基因组乳腺癌关联研究。这项研究的主要发现是，只有那些已知与普通人群中乳腺癌风险相关的基因座，包括FGFR 2（rs 2981575），在我们的高危人群中与BRCA 2相关的风险。ZNF 365（rs 16917302）和20号染色体（rs311499）上的两个新基因座被证明可以改变BRCA 2突变携带者的风险，尽管在全基因组水平上没有显著性。然而，ZNF 365基因座最近独立地与散发性肿瘤中的乳腺癌风险相关，突出了这种含锌指基因在乳腺癌发病机制中的潜在意义。我们的研究结果表明，其他常见变异不太可能对BRCA 2突变率产生强烈的修饰作用。
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 (λ) 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. The risk of breast cancer associated with BRCA2 mutations varies widely. To determine whether common genetic variants modify the penetrance of BRCA2 mutations, we conducted the first genome-wide association study of breast cancer among women with BRCA2 mutations using a two-stage approach. The major finding of the study is that only those loci known to be associated with breast cancer risk in the general population, including FGFR2 (rs2981575), modified BRCA2-associated risk in our high-risk population. Two novel loci, on chromosomes 10 in ZNF365 (rs16917302) and chromosome 20 (rs311499), were shown to modify risk in BRCA2 mutation carriers, although not at a genome-wide level of significance. However, the ZNF365 locus has recently independently been associated with breast cancer risk in sporadic tumors, highlighting the potential significance of this zinc finger-containing gene in breast cancer pathogenesis. Our results indicate that it is unlikely that other common variants have a strong modifying effect on BRCA2 penetrance.
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通讯作者：
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