Xinhua Liu1,2, Rongfang Qiu3,4,2, Min Xu3,4, Miaomiao Meng3,4, Siyu Zhao3,4, Jiansong Ji5,6, Yang Yang7,8,9. 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China. 2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. 3. Zhejiang Provincial Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, School of Medicine, Lishui Hospital of Zhejiang University, Lishui, 323000, Zhejiang, China. 4. Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. 5. Zhejiang Provincial Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, School of Medicine, Lishui Hospital of Zhejiang University, Lishui, 323000, Zhejiang, China. jijiansong@zju.edu.cn. 6. Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. jijiansong@zju.edu.cn. 7. Zhejiang Provincial Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, School of Medicine, Lishui Hospital of Zhejiang University, Lishui, 323000, Zhejiang, China. yangyang_8668@163.com. 8. Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China. yangyang_8668@163.com. 9. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. yangyang_8668@163.com.
Abstract
PURPOSE: Epigenetic regulation plays critical roles in cancer progression, and high-frequency mutations or expression variations in epigenetic regulators have been frequently observed in tumorigenesis, serving as biomarkers and targets for cancer therapy. Here, we aimed to explore the function of epigenetic regulators in breast cancer. METHODS: The mutational landscape of epigenetic regulators in breast cancer samples was investigated based on datasets from the Cancer Genome Atlas. The Kaplan-Meier method was used for survival analysis. RNA sequencing (RNA-seq) in MCF-7 cells transfected with control siRNA or KMT2C siRNA was performed. Quantitative reverse transcription-PCR and chromatin immunoprecipitation were used to validate the RNA-seq results. RESULTS: Among the 450 epigenetic regulators, KMT2C was frequently mutated in breast cancer samples. The tumor mutational burden (TMB) was elevated in breast cancer samples with KMT2C mutations or low KMT2C mRNA levels compared to their counterparts with wild-type KMT2C or high KMT2C mRNA levels. Somatic mutation and low expression of KMT2C were independently correlated with the poor overall survival (OS) and disease-free survival (DFS) of the breast cancer samples, respectively. RNA-seq analysis combined with chromatin immunoprecipitation and qRT-PCR assays revealed that the depletion of KMT2C remarkably affected the expression of DNA damage repair-related genes. More importantly, the low expression of KMT2C was related to breast cancer cell sensitivity to chemotherapy and longer OS of breast cancer patients who underwent chemotherapy. CONCLUSION: We conclude that KMT2C could serve as a potential biomarker of prognosis and chemotherapy sensitivity by affecting the DNA damage repair-related genes of breast cancer.
PURPOSE: Epigenetic regulation plays critical roles in cancer progression, and high-frequency mutations or expression variations in epigenetic regulators have been frequently observed in tumorigenesis, serving as biomarkers and targets for cancer therapy. Here, we aimed to explore the function of epigenetic regulators in breast cancer. METHODS: The mutational landscape of epigenetic regulators in breast cancer samples was investigated based on datasets from the Cancer Genome Atlas. The Kaplan-Meier method was used for survival analysis. RNA sequencing (RNA-seq) in MCF-7 cells transfected with control siRNA or KMT2C siRNA was performed. Quantitative reverse transcription-PCR and chromatin immunoprecipitation were used to validate the RNA-seq results. RESULTS: Among the 450 epigenetic regulators, KMT2C was frequently mutated in breast cancer samples. The tumor mutational burden (TMB) was elevated in breast cancer samples with KMT2C mutations or low KMT2C mRNA levels compared to their counterparts with wild-type KMT2C or high KMT2C mRNA levels. Somatic mutation and low expression of KMT2C were independently correlated with the poor overall survival (OS) and disease-free survival (DFS) of the breast cancer samples, respectively. RNA-seq analysis combined with chromatin immunoprecipitation and qRT-PCR assays revealed that the depletion of KMT2C remarkably affected the expression of DNA damage repair-related genes. More importantly, the low expression of KMT2C was related to breast cancer cell sensitivity to chemotherapy and longer OS of breast cancerpatients who underwent chemotherapy. CONCLUSION: We conclude that KMT2C could serve as a potential biomarker of prognosis and chemotherapy sensitivity by affecting the DNA damage repair-related genes of breast cancer.
Entities:
Keywords:
Breast cancer; Chemotherapy sensitivity; KMT2C; Mutation; Prognosis; TMB
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