Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Cancer Epidemiol Biomarkers Prev. 2021 Nov;30(11):2079-2087. doi: 10.1158/1055-9965.EPI-21-0400. Epub 2021 Sep 8.
The role of methylation in pancreatic cancer risk remains unclear. We integrated genome and methylome data to identify CpG sites (CpG) with the genetically predicted methylation to be associated with pancreatic cancer risk. We also studied gene expression to understand the identified associations.
Using genetic data and white blood cell methylation data from 1,595 subjects of European descent, we built genetic models to predict DNA methylation levels. After internal and external validation, we applied prediction models with satisfactory performance to the genetic data of 8,280 pancreatic cancer cases and 6,728 controls of European ancestry to investigate the associations of predicted methylation with pancreatic cancer risk. For associated CpGs, we compared their measured levels in pancreatic tumor versus benign tissue.
We identified 45 CpGs at nine loci showing an association with pancreatic cancer risk, including 15 CpGs showing an association independent from identified risk variants. We observed significant correlations between predicted methylation of 16 of the 45 CpGs and predicted expression of eight adjacent genes, of which six genes showed associations with pancreatic cancer risk. Of the 45 CpGs, we were able to compare measured methylation of 16 in pancreatic tumor versus benign pancreatic tissue. Of them, six showed differentiated methylation.
We identified methylation biomarker candidates associated with pancreatic cancer using genetic instruments and added additional insights into the role of methylation in regulating gene expression in pancreatic cancer development.
A comprehensive study using genetic instruments identifies 45 CpG sites at nine genomic loci for pancreatic cancer risk.
甲基化在胰腺癌风险中的作用尚不清楚。我们整合了基因组和甲基化组数据，以确定与胰腺癌风险相关的具有遗传预测甲基化的 CpG 位点（CpG）。我们还研究了基因表达，以了解所确定的关联。
使用来自 1595 名欧洲血统个体的遗传数据和白细胞甲基化数据，我们构建了遗传模型来预测 DNA 甲基化水平。经过内部和外部验证后，我们将具有令人满意性能的预测模型应用于 8280 例欧洲血统胰腺癌病例和 6728 例对照的遗传数据中，以研究预测的甲基化与胰腺癌风险的关联。对于相关的 CpG，我们比较了它们在胰腺肿瘤与良性组织中的测量水平。
我们在九个基因座确定了 45 个与胰腺癌风险相关的 CpG，其中包括 15 个与已确定的风险变异无关的 CpG。我们观察到 45 个 CpG 中 16 个的预测甲基化与 8 个相邻基因的预测表达之间存在显著相关性，其中 6 个基因与胰腺癌风险相关。在 45 个 CpG 中，我们能够比较胰腺肿瘤与良性胰腺组织中 16 个的测量甲基化。其中，有六个显示出分化的甲基化。
我们使用遗传工具鉴定了与胰腺癌相关的甲基化生物标志物候选物，并进一步深入了解了甲基化在调节胰腺癌发生中基因表达的作用。
一项使用遗传工具的综合研究确定了与胰腺癌风险相关的九个基因组位点的 45 个 CpG 位点。
