很少有研究探讨表观遗传年龄加速 (AA) 和DNA甲基化 (DNAm) 预测年龄与实际年龄之间的差异，并其与癌变组织和正常组织间的身体基因特征的关系，而在非欧洲人群中的研究更不足。本研究旨在研究DNAm年龄及其与中国香港乳腺癌 (BC) 患者乳腺组织的乳腺癌风险因素、亚型、体细胞基因组组合包括突变和拷贝数改变和其他衰老标志的关联。我们在中国香港 (HKBC) 的196例肿瘤和188例配对的邻近正常组织上进行了基因组宽 DNA甲基化分析，采用Illumina MethylationEPIC 芯片。DNAm年龄是基于Horvath的全组织时钟模型计算的。体细胞基因组特征基于RNA测序(RNASeq)、全外显子组测序(WES) 和全基因组测序(WGS) 的数据而得。使用Pearson相关系数 (r)、Kruskal-Wallis 检验和回归模型估计DNAm AA与体细胞特征和乳腺癌风险因素的关联。DNAm年龄在正常组织(Pearson r = 0.78, P < 2.2e-16)中与实际年龄的相关性比在肿瘤组织中 (Pearson r = 0.31, P = 7.8e-06) 更强烈。尽管总体上，DNAm年龄或AA在同一患者的组织中没有显著变化，但卵泡上皮型肿瘤表现出增加的DNAm AA (P = 0.004)，而HER2丰富/基底样肿瘤则表现出明显降低的DNAm AA (P = < .0001)，与亚型关联一致。与亚型关联一致，肿瘤DNAm AA与ESR1 (Pearson r = 0.39, P = 6.3e-06) 和PGR (Pearson r = 0.36, P = 2.4e-05) 基因表达呈正相关。与此一致，我们发现DNAm AA增加与更高的体重指数 (P = 0.039) 和更早的月经初潮年龄 (P = 0.035) 相关，这些因素与雌激素累积暴露有关。相反，表明广泛基因组不稳定性的变量(如TP53体细胞突变、高肿瘤突变/拷贝数改变负荷和同源重组缺陷)与低DNAm AA相关。我们的发现进一步揭示了东亚人群中与激素、基因组和表观遗传机制相互作用相关的乳腺组织老化的复杂性。 © 2023。这是美国政府的一项工作，不受美国版权保护;可能适用外国版权保护。

Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong.We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath's pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson's correlation (r), Kruskal-Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors.DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e-16) than in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e-06) and PGR (Pearson r = 0.36, P = 2.4e-05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA.Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.