Longitudinal study of leukocyte DNA methylation and biomarkers for cancer risk in older adults
Longitudinal study of leukocyte DNA methylation and biomarkers for cancer risk in older adults
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DOI：
10.1186/s40364-019-0161-3
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发表时间：
2019-05-28
影响因子：
11.1
通讯作者：
Mozhui, Khyobeni
中科院分区：
文献类型：
--
作者：
Bartlett, Alexandra H.;Liang, Jane W.;Mozhui, Khyobeni
DNA甲基化在生命过程中的变化可能提供癌症风险的指标。我们探讨了纵向变化的CpG甲基化从血液白细胞，和未来的癌症diagnosis.MethodsPeripheral血液样本在基线和随访访视从20名参与者的健康，衰老和身体成分前瞻性队列研究的可能性。使用Illumina Infinium Human MethylationEPIC（HM 850 K）microarray.ResultsGlobal Patterns在DNA甲基化从基于CpG的分析显示广泛的变化，随着时间的推移，在参与者发展癌症的细胞组成。到第6年访视时，CD 8 + T细胞比例下降（p值=0.02），而粒细胞水平增加（p值=0.04）与未患癌症的参与者相比，（无癌对有癌：CD 8 + T细胞为0.030.02对0.003 +/- 0.005;粒细胞为0.52 +/- 0.14对0.66 +/- 0.09）。表观全基因组分析确定了三个CpG，提示无癌组和有癌组之间差异甲基化的p值10（-5），包括位于MTA 3（与转移相关的基因）的CpG。在宽松的统计阈值（p值3x 10（-5））下，前10个癌症相关CpG包括一个参与mTOR通路的RPTOR附近的位点，以及候选肿瘤抑制基因REC 8，KCNQ 1和RENWIM 5。然而，仅RPTOR（cg 08129331）中的CpG在独立数据集中重复。从基线到第6年的个体内变化的分析发现，在RPTOR，REC 8和MAGNETWIM 5的甲基化的变化率之间的显着相关性，和时间到cancer diagnosis.Conclusion pid = Par 4的结果表明，细胞组成的变化解释了大部分的横截面和纵向变化的CpG甲基化。此外，特定CpG上的差异甲基化和纵向动力学可以提供癌症发展和/或进展的有力指标。特别是，我们强调RPTOR基因中的CpG甲基化作为癌症的潜在生物标志物，有待进一步验证。
BackgroundChanges in DNA methylation over the course of life may provide an indicator of risk for cancer. We explored longitudinal changes in CpG methylation from blood leukocytes, and likelihood of future cancer diagnosis.MethodsPeripheral blood samples were obtained at baseline and at follow-up visit from 20 participants in the Health, Aging and Body Composition prospective cohort study. Genome-wide CpG methylation was assayed using the Illumina Infinium Human MethylationEPIC (HM850K) microarray.ResultsGlobal patterns in DNA methylation from CpG-based analyses showed extensive changes in cell composition over time in participants who developed cancer. By visit year 6, the proportion of CD8+ T-cells decreased (p-value=0.02), while granulocytes cell levels increased (p-value=0.04) among participants diagnosed with cancer compared to those who remained cancer-free (cancer-free vs. cancer-present: 0.030.02 vs. 0.003 +/- 0.005 for CD8+ T-cells; 0.52 +/- 0.14 vs. 0.66 +/- 0.09 for granulocytes). Epigenome-wide analysis identified three CpGs with suggestive p-values 10(-5) for differential methylation between cancer-free and cancer-present groups, including a CpG located in MTA3, a gene linked with metastasis. At a lenient statistical threshold (p-value 3x10(-5)), the top 10 cancer-associated CpGs included a site near RPTOR that is involved in the mTOR pathway, and the candidate tumor suppressor genes REC8, KCNQ1, and ZSWIM5. However, only the CpG in RPTOR (cg08129331) was replicated in an independent data set. Analysis of within-individual change from baseline to Year 6 found significant correlations between the rates of change in methylation in RPTOR, REC8 and ZSWIM5, and time to cancer diagnosis.Conclusion p id=Par4 The results show that changes in cellular composition explains much of the cross-sectional and longitudinal variation in CpG methylation. Additionally, differential methylation and longitudinal dynamics at specific CpGs could provide powerful indicators of cancer development and/or progression. In particular, we highlight CpG methylation in the RPTOR gene as a potential biomarker of cancer that awaits further validation.