Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Av. de la Investigación 11, 18007, Granada, Spain.
GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, Av. de la Ilustración 114, 18007, Granada, Spain.
BMC Med Genomics. 2022 Mar 4;15(1):45. doi: 10.1186/s12920-022-01183-2.
DNA methylation (DNAm) age metrics have been widely accepted as an epigenetic biomarker for biological aging and disease. The purpose of this study is to assess whether or not individuals carrying Lynch Syndrome-associated mutations are affected in their rate of biological aging, as measured by the epigenetic clock.
Genome-wide bisulfite DNA sequencing data were generated using DNA from CD4 + T-cells obtained from peripheral blood using 27 patient samples from Lynch syndrome families. Horvath's DNAm age model based on penalized linear regression was applied to estimate DNAm age from patient samples with distinct clinical and genetic characteristics to investigate cancer mutation-related aging effects.
Both Lynch mutation carriers and controls exhibited high variability in their estimated DNAm age, but regression analysis showed steeper slope for the Lynch mutation carriers. Remarkably, six Lynch Syndrome-associated mutation carriers showed a strong correlation to the control group, and two sisters carrying Lynch Syndrome-associated mutations, with no significant difference in lifestyle and similar chronological age, were assigned very different DNAm age.
Future studies will be required to explore, in larger patient populations, whether specific epigenetic age acceleration is predictive of time-to-cancer development, treatment response, and survival. Epigenetic clock DNAm metrics may be affected by the presence of cancer mutations in the germline, and thus show promise of potential clinical utility for stratified surveillance strategies based on the relative risk for imminent emergence of tumor lesions in otherwise healthy Lynch Syndrome-associated mutation carriers.
DNA 甲基化（DNAm）年龄指标已被广泛接受为生物衰老和疾病的表观遗传生物标志物。本研究旨在评估携带林奇综合征相关突变的个体是否会影响其生物衰老速度，这是通过表观遗传时钟来衡量的。
使用来自林奇综合征家族的 27 个患者样本的外周血中的 CD4+T 细胞的 DNA，生成全基因组亚硫酸氢盐 DNA 测序数据。应用 Horvath 的基于惩罚线性回归的 DNAm 年龄模型，从具有不同临床和遗传特征的患者样本中估计 DNAm 年龄，以研究癌症突变相关的衰老效应。
携带林奇突变的个体和对照组的估计 DNAm 年龄都有很大的变异性，但回归分析显示林奇突变携带者的斜率更陡峭。值得注意的是，六名携带林奇综合征相关突变的患者与对照组表现出很强的相关性，两名携带林奇综合征相关突变的姐妹，生活方式没有显著差异，且年龄相同，她们的 DNAm 年龄却存在明显差异。
需要进一步在更大的患者群体中进行研究，以探索特定的表观遗传年龄加速是否可预测癌症发展、治疗反应和生存时间。生殖系中存在癌症突变可能会影响表观遗传时钟的 DNAm 指标，因此有望为基于相对风险的分层监测策略提供潜在的临床应用，以便在其他方面健康的携带林奇综合征相关突变的个体中，对即将出现的肿瘤病变进行监测。
