Regional methylome profiling reveals dynamic epigenetic heterogeneity and convergent hypomethylation of stem cell quiescence-associated genes in breast cancer following neoadjuvant chemotherapy

Cell & Bioscience

卷:9

Yi Tang¹  Juan Huang¹  Xitu Luo¹  Detu Zhu²  Yumei Luo³  Yaoyong Chen³  Xiujie Sheng³  Xiaofang Sun³  Lingxia Ge³ 

[1] Department of General Surgery, The Third Affiliated Hospital of Guangzhou Medical University;

[2] Department of Genetic Medicine, Weill Cornell Medical College;

[3] Key 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;

关键词: Breast cancer;    Neoadjuvant chemotherapy;    Chemoresistance;    DNA methylation;    Epigenetic heterogeneity;    High-density methylation microarray;   

DOI  :  10.1186/s13578-019-0278-y

来源: DOAJ

【 摘 要 】

Abstract Background 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. Methods 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). Results 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. Conclusions 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.

【 授权许可】

Unknown