A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival.
A BRCA1-mutation associated DNA methylation signature in blood cells predicts sporadic breast cancer incidence and survival.
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DOI：
10.1186/gm567
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发表时间：
2014
期刊：
影响因子：
12.3
通讯作者：
Widschwendter M
中科院分区：
文献类型：
--
作者：
Anjum S;Fourkala EO;Zikan M;Wong A;Gentry-Maharaj A;Jones A;Hardy R;Cibula D;Kuh D;Jacobs IJ;Teschendorff AE;Menon U;Widschwendter M
BRCA 1突变携带者患乳腺癌的风险为85%，但患非遗传性乳腺癌的风险很难评估。我们的目标是测试来自BRCA 1突变携带者的DNA甲基化（DNAme）签名是否能够预测非遗传性乳腺癌。在病例/对照设置（72名BRCA 1突变携带者和72名BRCA 1/2野生型对照）中，在Illumina 27 k甲基化阵列上对血细胞DNA样品进行分析。使用弹性网络分类算法，在两个队列中导出并测试了BRCA 1突变DNAme签名：（1）NSHD（19例乳腺癌在样本捐赠后12年内发生，77例对照）和（2）UKCTOCS试验（119例雌激素受体阳性乳腺癌在样本捐赠后5年内发生，122例对照）。我们发现，将我们的基于血液的BRCA 1突变DNAme签名应用于NSHD女性的血细胞DNA导致0.65的受试者工作特征（ROC）曲线下面积（AUC）（95%CI 0.51至0.78，P = 0.02），这在来自相同个体的口腔细胞中没有验证。在UKCTOCS志愿者的血液DNA中应用签名导致AUC为0.57（95% CI 0.50至0.64; P = 0.03），并且与家族史或任何其他已知的风险因素无关。重要的是，BRCA 1突变DNA标签能够预测乳腺癌死亡率（AUC = 0.67; 95% CI 0.51至0.83; P = 0.02）。我们还发现BRCA 1突变携带者中高甲基化的1,074个CpG显著富集干细胞polycomb组靶基因（P <10-20）。来自BRCA 1携带者的DNAme签名能够在诊断前几年预测乳腺癌风险和死亡。未来的研究可能需要关注上皮细胞中的DNAme谱，以达到预防措施或早期检测策略所需的AUC阈值。
BRCA1 mutation carriers have an 85% risk of developing breast cancer but the risk of developing non-hereditary breast cancer is difficult to assess. Our objective is to test whether a DNA methylation (DNAme) signature derived from BRCA1 mutation carriers is able to predict non-hereditary breast cancer. In a case/control setting (72 BRCA1 mutation carriers and 72 BRCA1/2 wild type controls) blood cell DNA samples were profiled on the Illumina 27 k methylation array. Using the Elastic Net classification algorithm, a BRCA1-mutation DNAme signature was derived and tested in two cohorts: (1) The NSHD (19 breast cancers developed within 12 years after sample donation and 77 controls) and (2) the UKCTOCS trial (119 oestrogen receptor positive breast cancers developed within 5 years after sample donation and 122 controls). We found that our blood-based BRCA1-mutation DNAme signature applied to blood cell DNA from women in the NSHD resulted in a receiver operating characteristics (ROC) area under the curve (AUC) of 0.65 (95% CI 0.51 to 0.78, P = 0.02) which did not validate in buccal cells from the same individuals. Applying the signature in blood DNA from UKCTOCS volunteers resulted in AUC of 0.57 (95% CI 0.50 to 0.64; P = 0.03) and is independent of family history or any other known risk factors. Importantly the BRCA1-mutation DNAme signature was able to predict breast cancer mortality (AUC = 0.67; 95% CI 0.51 to 0.83; P = 0.02). We also found that the 1,074 CpGs which are hypermethylated in BRCA1 mutation carriers are significantly enriched for stem cell polycomb group target genes (P <10-20). A DNAme signature derived from BRCA1 carriers is able to predict breast cancer risk and death years in advance of diagnosis. Future studies may need to focus on DNAme profiles in epithelial cells in order to reach the AUC thresholds required of preventative measures or early detection strategies.
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影响因子：
3.5
作者：
Flanagan JM;Munoz-Alegre M;Henderson S;Tang T;Sun P;Johnson N;Fletcher O;Dos Santos Silva I;Peto J;Boshoff C;Narod S;Petronis A
通讯作者：
Petronis A
影响因子：
50.3
作者：
O'Hagan HM;Wang W;Sen S;Destefano Shields C;Lee SS;Zhang YW;Clements EG;Cai Y;Van Neste L;Easwaran H;Casero RA;Sears CL;Baylin SB
通讯作者：
Baylin SB
影响因子：
4.8
作者：
Newson, Roger
通讯作者：
Newson, Roger
影响因子：
56.9
作者：
Cui, HM;Cruz-Correa, M;Feinberg, AP
通讯作者：
Feinberg, AP
影响因子：
64.5
作者：
Lee, TI;Jenner, RG;Young, RA
通讯作者：
Young, RA