University of Kentucky Markey Cancer Center, 800 Rose Street, Lexington, KY, 40536, USA.
Susan G. Komen Tissue Bank at Indiana University Simon Cancer Center, Indianapolis, IN, USA.
Clin Epigenetics. 2020 Mar 12;12(1):45. doi: 10.1186/s13148-020-00834-4.
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) 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). 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 and 1.0 × 10, respectively). Both HER2+ and hormone-receptor positive subtypes demonstrated significant acceleration in DNAm ages (p = 0.04 and 3.8 × 10, 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.
DNA 甲基化（DNAm）年龄已被广泛接受为生物衰老的表观遗传生物标志物。新出现的证据表明，DNAm 年龄可能具有组织特异性，女性乳房组织的衰老速度快于身体的其他部位。Horvath 时钟可以估算多个组织的 DNAm 年龄，但在乳房组织中校准效果不佳。我们旨在开发一种模型来估算乳房组织特异性的 DNAm 年龄。
为 459 个正常、107 个肿瘤和 45 对配对的相邻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 个乳房组织特异性时钟 CpG，并开发了一种模型来估算乳房组织特异性的 DNAm 年龄。该模型应用于不同类型的乳房组织和具有不同临床特征的肿瘤中，以研究与癌症相关的衰老效应。
在正常乳房组织中，我们估算的乳房组织特异性 DNAm 年龄与实际年龄高度相关（r = 0.88；p = 2.9×10）。乳房肿瘤组织样本表现出正的表观遗传年龄加速，即 DNAm 年龄比相应的实际年龄平均大 7 岁（p = 1.8×10）。在年龄匹配的分析中，肿瘤乳房组织在 DNAm 年龄上比相邻正常和正常乳房组织分别大 12 岁和 13 岁（p = 4.0×10 和 1.0×10）。HER2+和激素受体阳性亚型的 DNAm 年龄均明显加速（p = 0.04 和 3.8×10），而三阴性乳腺癌则未观察到明显的 DNAm 年龄加速。我们观察到随着乳腺癌分级的增加，表观遗传年龄加速呈非线性模式。此外，早期阶段的肿瘤表现出正的表观遗传年龄加速（p = 0.003），而晚期阶段的肿瘤表现出非显著的负表观遗传年龄加速（p = 0.10）。
该模型的预期应用范围广泛，并已证明为乳腺癌肿瘤组织中与癌症相关的衰老效应提供了有生物学意义的结果。需要进一步研究以探讨乳房组织特异性表观遗传年龄加速是否可预测乳腺癌的发生、治疗反应和生存，以及该模型是否可扩展到血液样本的临床应用。
