衰老和癌症风险的 DNA 甲基化算法的关联：来自前瞻性队列研究的结果。

Associations of DNA methylation algorithms of aging and cancer risk: Results from a prospective cohort study.

机构信息

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; Network Aging Research, Heidelberg University, Bergheimer Straße 20, 69115 Heidelberg, Germany.

出版信息

EBioMedicine. 2022 Jul;81:104083. doi: 10.1016/j.ebiom.2022.104083. Epub 2022 May 27.

DOI:10.1016/j.ebiom.2022.104083

PMID:35636319

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9157462/

Abstract

BACKGROUND

Previous studies have shown that three DNA methylation (DNAm) based algorithms of aging, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), to be strong predictors of mortality and aging related outcomes. We aimed to investigate if and to what extent these algorithms predict cancer.

METHODS

In four subsets (n = 727, 1003, 910, and 412) of a population-based cohort from Germany, DNA methylation in whole blood was measured using the Infinium Methylation EPIC BeadChip kit or the Infinium HumanMethylation450K BeadChip Assay (Illumina.Inc, San Diego, CA, USA). AgeAccelPheno, AgeAccelGrim, and a revised MRscore based on 8 CpGs only (MRscore-8CpGs), were calculated. Hazard ratios (HRs) were calculated to assess associations of the three DNAm algorithms with total cancer risk and risk of invasive breast, lung, prostate, and colorectal cancer incidence.

FINDINGS

During 17 years of follow-up, a total of 697 malignant tumors (thereof breast cancer = 75, lung cancer = 146, prostate cancer = 114, colorectal cancer = 155) were observed. All three algorithms showed strong positive associations with lung cancer risk in a dose response manner, with adjusted HRs per SD increase in AgeAccelPheno, AgeAccelGrim, and MRscore-8CpGs, of 1·37 (1·03-1·82), 1·74 (1·11-2·73), and 2·06 (1·39-3·06), respectively. By contrast, strong inverse associations were seen with breast cancer risk [adjusted HRs 0·65 (0·49-0·86), 0·45 (0·25-0·80), and 0·42 (0·25-0·70), respectively]. Weak positive associations of MRscore-8CpGs were seen with total cancer risk.

INTERPRETATION

The DNAm algorithms, particularly the MRscore-8CpGs, have potential to contribute to site-specific cancer risk prediction.

FUNDING

The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany), and the Saarland State Ministry of Health, Social Affairs, Women and the Family (Saarbrücken, Germany). The work of Xiangwei Li was supported by a grant from Fondazione Cariplo (Bando Ricerca Malattie invecchiamento, #2017-0653).

摘要

背景

先前的研究表明，三种基于 DNA 甲基化（DNAm）的衰老算法，即 DNAm PhenoAge 加速（AgeAccelPheno）、DNAm GrimAge 加速（AgeAccelGrim）和死亡率风险评分（MRscore），是死亡率和与衰老相关结局的强有力预测因子。我们旨在研究这些算法是否以及在何种程度上可以预测癌症。

方法

在来自德国的一项基于人群的队列的四个子集中（n=727、1003、910 和 412），使用 Infinium Methylation EPIC BeadChip 试剂盒或 Infinium HumanMethylation450K BeadChip 检测试剂盒（Illumina.Inc，圣地亚哥，CA，美国）测量全血中的 DNA 甲基化。计算 AgeAccelPheno、AgeAccelGrim 和基于 8 个 CpG 的修订版 MRscore（MRscore-8CpGs）。计算危害比（HRs）以评估三种 DNAm 算法与总癌症风险以及侵袭性乳腺癌、肺癌、前列腺癌和结直肠癌发病风险的相关性。

结果

在 17 年的随访期间，共观察到 697 例恶性肿瘤（乳腺癌=75 例，肺癌=146 例，前列腺癌=114 例，结直肠癌=155 例）。所有三种算法均与肺癌风险呈显著正相关，呈剂量反应关系，AgeAccelPheno、AgeAccelGrim 和 MRscore-8CpGs 每增加一个标准差，HR 分别为 1.37（1.03-1.82）、1.74（1.11-2.73）和 2.06（1.39-3.06）。相比之下，与乳腺癌风险呈强负相关[调整后的 HR 分别为 0.65（0.49-0.86）、0.45（0.25-0.80）和 0.42（0.25-0.70）]。MRscore-8CpGs 与总癌症风险呈弱正相关。