Luo Yumei, Huang Juan, Tang Yi, Luo Xitu, Ge Lingxia, Sheng Xiujie, Sun Xiaofang, Chen Yaoyong, Zhu Detu
1Key Laboratory for Major Obstetric Diseases of Guangdong Province and Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150 China.
2Department of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150 China.
Cell Biosci. 2019 Feb 7;9:16. doi: 10.1186/s13578-019-0278-y. eCollection 2019.
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~ 30% of patients with breast cancer. However, aberrant DNA methylation alterations are frequent events during breast cancer progression and acquisition of chemoresistance. We aimed to characterize the inter- and intra-tumor methylation heterogeneity (MH) in breast cancer following NAC.
DNA methylation profiles of spatially separated regions of breast tumors before and after NAC treatment were investigated using high-density methylation microarray. Methylation levels of genes of interest were further examined using multiplexed MethyLight droplet digital PCR (ddPCR).
We have discovered different levels of intra-tumor MH in breast cancer patients. Moreover, NAC dramatically altered the methylation profiles and such changes were highly heterogeneous between the patients. Despite the high inter-patient heterogeneity, we identified that stem cell quiescence-associated genes ALDH1L1, HOPX, WNT5A and SOX9 were convergently hypomethylated across all the samples after NAC treatment. Furthermore, by using MethyLight ddPCR, we verified that the methylation levels of these 4 genes were significantly lower in breast tumor samples after NAC than those before NAC.
Our study has revealed that NAC dramatically alters epigenetic heterogeneity in breast cancer and induces convergent hypomethylation of stem cell quiescence-associated genes, ALDH1L1, HOPX, WNT5A and SOX9, which can potentially be developed as therapeutic targets or biomarkers for chemoresistance.
新辅助化疗（NAC）可使约30%的乳腺癌患者达到病理完全缓解（pCR）。然而，异常的DNA甲基化改变是乳腺癌进展和获得化疗耐药过程中的常见事件。我们旨在表征NAC治疗后乳腺癌肿瘤间和肿瘤内的甲基化异质性（MH）。
使用高密度甲基化微阵列研究NAC治疗前后乳腺肿瘤空间分离区域的DNA甲基化谱。使用多重甲基化荧光定量液滴数字PCR（ddPCR）进一步检测感兴趣基因的甲基化水平。
我们发现乳腺癌患者肿瘤内存在不同程度的MH。此外，NAC显著改变了甲基化谱，且这些变化在患者之间高度异质。尽管患者间异质性较高，但我们发现NAC治疗后所有样本中，干细胞静止相关基因ALDH1L1、HOPX、WNT5A和SOX9均发生了趋同的低甲基化。此外，通过甲基化荧光定量ddPCR，我们证实NAC治疗后乳腺肿瘤样本中这4个基因的甲基化水平显著低于NAC治疗前。
我们的研究表明，NAC显著改变了乳腺癌的表观遗传异质性，并诱导了干细胞静止相关基因ALDH1L1、HOPX、WNT5A和SOX9的趋同低甲基化，这些基因有可能被开发为化疗耐药的治疗靶点或生物标志物。
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