DNA methylation (DNAm) age has been widely accepted as an epigenetic biomarker for biological aging. Emerging evidence suggests that DNAm age can be tissue-specific and female breast tissue ages faster than other parts of the body. The Horvath clock, which estimates DNAm age across multiple tissues, has been shown to be poorly calibrated in breast issue. We aim to develop a model to estimate breast tissue-specific DNAm age. Genome-wide DNA methylation sequencing data were generated for 459 normal, 107 tumor, and 45 paired adjacent-normal breast tissue samples. We determined a novel set of 286 breast tissue-specific clock CpGs using penalized linear regression and developed a model to estimate breast tissue-specific DNAm age. The model was applied to estimate breast tissue-specific DNAm age in different breast tissue types and in tumors with distinct clinical characteristics to investigate cancer-related aging effects. Our estimated breast tissue-specific DNAm age was highly correlated with chronological age (r = 0.88; p = 2.9 × 10−31) in normal breast tissue. Breast tumor tissue samples exhibited a positive epigenetic age acceleration, where DNAm age was on average 7 years older than respective chronological age (p = 1.8 × 10−8). In age-matched analyses, tumor breast tissue appeared 12 and 13 years older in DNAm age than adjacent-normal and normal breast tissue (p = 4.0 × 10−6 and 1.0 × 10−6, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10−6, respectively), while no apparent DNAm age acceleration was observed for triple-negative breast tumors. We observed a non-linear pattern of epigenetic age acceleration with breast tumor grade. In addition, early-staged tumors showed a positive epigenetic age acceleration (p = 0.003) while late-staged tumors exhibited a non-significant negative epigenetic age acceleration (p = 0.10). The intended applications for this model are wide-spread and have been shown to provide biologically meaningful results for cancer-related aging effects in breast tumor tissue. Future studies are warranted to explore whether breast tissue-specific epigenetic age acceleration is predictive of breast cancer development, treatment response, and survival as well as the clinical utility of whether this model can be extended to blood samples.

中文翻译：

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使用下一代测序数据估算乳房组织特异性DNA甲基化年龄。

DNA甲基化（DNAm）年龄已被广泛接受为生物衰老的表观遗传标记。新兴证据表明，DNAm的年龄可能是组织特异性的，女性乳房组织的衰老速度要快于身体其他部位。Horvath时钟可估计多种组织中DNAm的年龄，但已证明在乳房问题中校准不佳。我们旨在建立一个模型来估计特定于乳房组织的DNAm年龄。为459个正常，107个肿瘤和45个配对的正常乳房组织样本生成了全基因组DNA甲基化测序数据。我们使用惩罚线性回归确定了一组新的286乳腺组织特异性时钟CpG，并开发了一个模型来估算乳腺组织特异性DNAm年龄。该模型用于评估不同乳腺组织类型和具有不同临床特征的肿瘤中乳腺组织特异性DNAm的年龄，以研究与癌症相关的衰老效应。我们估计的乳腺组织特异性DNAm年龄与正常乳腺组织中的年龄高度相关（r = 0.88; p = 2.9×10−31）。乳腺肿瘤组织样本显示出正的表观遗传年龄加速，其中DNAm年龄平均比各自的年代年龄大7岁（p = 1.8×10-8）。在年龄匹配的分析中，肿瘤乳腺组织的DNAm年龄比相邻的正常乳腺组织和正常乳腺组织分别大12和13岁（分别为p = 4.0×10-6和1.0×10-6）。HER2 +和激素受体阳性亚型在DNAm年龄均表现出显着加速（分别为p = 0.04和3.8×10-6），对于三阴性乳腺癌，没有观察到明显的DNAm年龄加速。我们观察到表观遗传年龄加速与乳腺癌分级的非线性关系。另外，早期肿瘤表现出正的表观遗传年龄加速（p = 0.003），而晚期肿瘤表现出无显着的负表观遗传年龄加速（p = 0.10）。该模型的预期应用广泛，并且已显示出可为乳腺癌组织中与癌症相关的衰老影响提供生物学上有意义的结果。有必要进行进一步的研究，以探索特定于乳腺组织的表观遗传年龄的加速是否可预测乳腺癌的发生，治疗反应和生存率，以及该模型是否可扩展至血液样本的临床实用性。