大规模甲基化分析揭示了其作为乳腺癌生物标志物的潜力。
Large-scale analysis of methylation reveals its potential as biomarker for breast cancer.
机构信息
Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, BE-2650 Edegem, Antwerp Belgium.
Center for Oncological Research, University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, BE-2610 Wilrijk, Antwerp Belgium.
出版信息
Clin Epigenetics. 2018 Apr 11;10:51. doi: 10.1186/s13148-018-0479-y. eCollection 2018.
BACKGROUND
Breast cancer is the most frequent cancer among women worldwide. Biomarkers for early detection and prognosis of these patients are needed. We hypothesized that , () may be a valuable biomarker, based upon strong indications for its role as tumor suppressor gene and its function in regulated cell death. In this study, we aimed to analyze methylation and expression in the largest breast cancer cohort to date using publicly available data from TCGA, in order to further unravel the role of as detection and/or prognostic marker in breast cancer. We analyzed Infinium HumanMethylation450k data, covering 22 different CpGs in the gene (668 breast adenocarcinomas and 85 normal breast samples) and expression (Agilent 244K Custom Gene Expression: 476 breast adenocarcinomas and 56 normal breast samples; RNA-sequencing: 666 breast adenocarcinomas and 71 normal breast samples).
RESULTS
methylation and expression were significantly different between breast cancer and normal breast samples. Overall, breast cancer samples showed higher methylation in the putative gene promoter compared to normal breast samples, whereas in the gene body and upstream of the putative gene promoter, the opposite is true. Furthermore, methylation, in 10 out of 22 CpGs, and expression were significantly higher in lobular compared to ductal breast cancers. An important result of this study was the identification of a combination of one CpG in the gene promoter (CpG07504598) and one CpG in the gene body (CpG12922093) of , which was able to discriminate between breast cancer and normal breast samples (AUC = 0.93). This model was externally validated in three independent datasets. Moreover, we showed that estrogen receptor state is associated with methylation and expression. Finally, we were able to find a significant effect of gene body methylation on a 5-year overall survival time.
CONCLUSIONS
We conclude that methylation shows strong potential as detection and prognostic biomarker for breast cancer.
背景
乳腺癌是全世界女性最常见的癌症。需要寻找用于此类患者早期检测和预后的生物标志物。我们推测，基于其作为肿瘤抑制基因的作用及其在调控细胞死亡中的功能，()可能是一种有价值的生物标志物。在这项研究中，我们旨在使用 TCGA 提供的公开数据，分析迄今为止最大的乳腺癌队列中的 甲基化和表达，以进一步揭示 作为乳腺癌检测和/或预后标志物的作用。我们分析了 Infinium HumanMethylation450k 数据，该数据覆盖了 基因中的 22 个不同 CpG（668 例乳腺腺癌和 85 例正常乳腺样本）和 表达（Agilent 244K Custom Gene Expression：476 例乳腺腺癌和 56 例正常乳腺样本；RNA-seq：666 例乳腺腺癌和 71 例正常乳腺样本）。
结果
乳腺癌与正常乳腺样本之间的 甲基化和表达存在显著差异。总体而言，与正常乳腺样本相比，乳腺癌样本中在假定的基因启动子处的 甲基化更高，而在基因体中和假定的基因启动子上游，情况则相反。此外，在 10 个 CpG 中，有 10 个 CpG 的 甲基化和表达在小叶癌中比在导管癌中更高。本研究的一个重要结果是鉴定了 基因启动子中的一个 CpG（CpG07504598）和基因体中的一个 CpG（CpG12922093）的组合，该组合能够区分乳腺癌和正常乳腺样本（AUC = 0.93）。该模型在三个独立的数据集进行了外部验证。此外，我们表明雌激素受体状态与 甲基化和表达相关。最后，我们能够发现 基因体甲基化对 5 年总生存时间有显著影响。
结论
我们得出结论， 甲基化显示出作为乳腺癌检测和预后生物标志物的强大潜力。
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