Environmental Exposure and DNA Damage

环境暴露和 DNA 损伤

• 批准号: 10253778
• 负责人: JACK A TAYLOR
• 金额: $ 145.46万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253778
• 关键词: Area; Area Under Curve; Biological; Blood; Cancer-Predisposing Gene; Candidate Disease Gene; Cannabis; Carcinogens; Characteristics; Classification; Clinical; Clinical Research; Cohort Studies; CpG Islands; DNA; DNA Damage; DNA Methylation; DNA Modification Process; Data; Data Set; Detection; Diagnosis; Dyes; Early Diagnosis; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Event; Genes; Genome; Health; Individual; Italy; Life Cycle Stages; Measurement; Measures; Methylation; Modification; Molecular; Noise; Nucleic Acid Regulatory Sequences; Pathway Analysis; Pathway interactions; Pattern; Prevention; Publishing; Reporting; Research; Research Design; Sampling; Single Nucleotide Polymorphism; Sister; Site; Testing; Time; Variant; Work; base; bead chip; candidate marker; environmental agent; epidemiology study; epigenome; epigenome-wide association studies; genetic association; genome-wide; improved; malignant breast neoplasm; marijuana use; meetings; outcome forecast; peripheral blood; promoter; prospective; response; tool; tumor

Peripheral blood DNA methylation may be associated with breast cancer, but studies of candidate genes and global and genome-wide DNA methylation have been inconsistent. We performed an epigenome-wide study using Infinium HumanMethylation450 BeadChips with prospectively collected blood DNA samples from the Sister Study (1552 cases, 1224 subcohort). We identified 9601 CpG markers associated with invasive breast cancer (false discovery rate = q < 0.01), with 510 meeting a strict Bonferroni correction threshold (10-7). A total of 2095 of these CpGs replicated in the independent EPIC-Italy dataset, including 144 meeting the Bonferroni threshold. Most dmCpGs showed lower methylation in invasive cases. In case-only analysis, methylation was statistically significantly associated with time to diagnosis for 892 (42.6%) of the dmCpGs. Analyses based on genetic association suggest that methylation differences are likely a consequence rather than a cause of breast cancer. Pathway analysis shows enrichment of breast cancer-related gene pathways, and dmCpGs are overrepresented in known breast cancer susceptibility genes. Our findings suggest that the DNA methylation profile of blood starts to change in response to invasive breast cancer years before the tumor is clinically detected. Cannabis use is highly prevalent and is associated with adverse and beneficial effects. DNA methylation (DNAm) is candidate marker for cannabis exposure, yet no blood-based epigenome-wide association studies (EWAS) exist. We conducted an EWAS of lifetime cannabis use using blood-based DNAm data from this same case-cohort study of breast cancer. We identified and replicated an association with lifetime cannabis use at one CpG site in the gene CEMIP (p = 3.3 10-8 ). We found no overlap between published blood-based cis-meQTLs of this CpG and reported lifetime cannabis use-associated single nucleotide polymorphism (SNPs; p < .05), suggesting that the observed DNAm difference was driven by cannabis exposure. We also developed a multi-CpG classifier of lifetime cannabis use using penalized regression of top EWAS CpGs. The resulting 50-CpG classifier produced an area under the curve (AUC) = 0.74 (p = 2.00 10-5 ) in the discovery sample and AUC = 0.54 p = 2.87 10-2 ) in the replication sample. Our EWAS findings provide evidence that blood-based DNAm is associated with lifetime cannabis use. Our work makes wide use of Illumina BeadChips. Several studies have reported that many probes on these arrays have poor reliability which is measured by intra-class correlation coefficients (ICC). We describe the characteristics of ICC across the genome, within and between studies, and across different array platforms. We find that with raw data only 22.5% of the CpGs on 450 K array have 'acceptable' ICCs (>0.5). Data preprocessing steps, such as background correction and dye bias correction, can reduce technical noise and improve the percentage to 38.5%. Similar to previous studies, we found that ICC is associated with CpG methylation level such that 83% of CpGs with intermediate methylation (0.1< beta-value <0.9) have acceptable ICCs, whereas only 21% of CpGs with low or high methylation (beta-value <0.1 or >0.9) have acceptable ICCs. ICC is also correlated with CpG methylation variance; after mutual adjustment for beta-value and variance, only variance remains correlated. Many CpGs with poor ICCs (<0.5) are located in biologically important regulatory regions, including gene promoters and CpG islands. Poor ICC at these sites appears to be a consequence of low biologic variation among individuals rather than increased technical measurement variation. ICCs quality classifications are highly concordant across different array platforms and across different studies. CpGs with acceptable ICC have higher study power and are more commonly reported in published epigenome-wide studies. We find that ICC can be reliably estimated with 30 pairs of duplicate samples.

外周血DNA甲基化可能与乳腺癌有关，但对候选基因以及全球和全基因组DNA甲基化的研究一直不一致。我们使用Infinium HumanMylation450 BeadChips进行了一项表观基因组研究，前瞻性地从Sister研究中收集了血液DNA样本(1552例，1224个子队列)。我们确定了9601个与浸润性乳腺癌相关的CpG标记(错误发现率=Q&lt；0.01)，其中510个符合严格的Bonferroni校正阈值(10-7)。在独立的EPIC-意大利数据集中，共有2095个这样的CPGS被复制，其中144个达到Bonferroni阈值。在侵袭性病例中，大多数dmCpG的甲基化水平较低。在仅病例分析中，在892例(42.6%)的dmCpG中，甲基化与诊断时间显著相关。基于遗传关联的分析表明，甲基化差异可能是乳腺癌的结果，而不是原因。通路分析显示乳腺癌相关基因通路丰富，dmCpGs在已知的乳腺癌易感基因中过度表达。我们的发现表明，在临床检测到肿瘤的前几年，血液中的DNA甲基化特征开始改变，以应对浸润性乳腺癌。 大麻的使用非常普遍，并与不利和有益的影响有关。DNA甲基化(DNaM)是大麻暴露的候选标记，但尚不存在基于血液的表观基因组全关联研究(Ewas)。我们使用来自同一乳腺癌病例队列研究的基于血液的dNaM数据进行了一项终生大麻使用的EWA。我们在CEMIP基因的一个CpG位点发现并复制了与终生大麻使用的关联(p=3.310-8)。我们发现这种CpG的基于血液的顺式-meQTL和报道的终生大麻使用相关单核苷酸多态(SNPs；p&lt；0.05)之间没有重叠，这表明观察到的dNaM差异是由大麻暴露引起的。我们还开发了一种终身大麻使用的多CpG分类器，使用顶端EWASCPGS的惩罚性回归。得到的50-CpG分类器在发现样本中产生曲线下面积(AUC)=0.74(p=2.00 10-5)，在复制样本中产生AUC=0.54 p=2.87 10-2)。我们的Ewas发现提供了基于血液的dNaM与终生大麻使用相关的证据。 我们的工作广泛使用了Illumina BeadChips。一些研究已经报道，这些阵列上的许多探针的可靠性较差，这是通过类内相关系数(ICC)来衡量的。我们描述了跨基因组、在研究内部和研究之间以及跨不同阵列平台的ICC的特征。我们发现，使用原始数据，在450K阵列上，只有22.5%的CPG具有可接受的ICC(&gt；0.5)。数据的前处理步骤，如背景校正和染料偏置校正，可以降低技术噪声，使百分比提高到38.5%。与以前的研究相似，我们发现ICC与CpG甲基化水平有关，因此83%的中度甲基化的CPGS具有可接受的ICCs，而只有21%的低甲基化或高甲基化的CPGS具有可接受的ICCS。ICC还与CpG甲基化变异相关；在相互调整Beta值和方差后，只有变异保持相关。许多ICC较差的CPGS位于重要的生物调控区域，包括基因启动子和CpG岛。这些部位较差的ICC似乎是个体间生物变异较低的结果，而不是技术测量变异增加的结果。ICCS质量分类在不同的阵列平台和不同的研究中高度一致。具有可接受的ICC的CPGS具有更高的研究能力，并且在已发表的表观基因组研究中更常见。我们发现，使用30对重复样本可以可靠地估计ICC。