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KMT2C is a potential biomarker of prognosis and chemotherapy sensitivity in breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Data Availability

The datasets generated and/or analyzed during the current study are available in the TCGA repository. https://portal.gdc.cancer.gov/

Abbreviations

COSMIC:

Catalogue of somatic mutations in cancer

ChIP:

Chromatin immunoprecipitation

DAVID:

Database for annotation, visualization, and integrated analysis

DEG:

Differential expression gene

DFS:

Disease-free survival

DR:

DNA replication

FC:

Fold change

GO:

Gene ontology

HR:

Homologous recombination

KEGG:

Kyoto encyclopedia of genes and genomes

MCE:

MedChemExpress

MMR:

Mismatch repair

MSK-IMPACT:

Memorial sloan kettering-integrated mutation profiling of actionable cancer targets

OS:

Overall survival

qRT-PCR:

Quantitative reverse transcription-PCR

RNA-seq:

RNA sequencing

TCGA:

The cancer genome atlas

TMB:

Tumor mutational burden

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Funding

This study was supported by the National Natural Science Foundation of China (Grant Number 81803778 to JJS), a grant (2020KY1085 to QRF) from the Medical and Health Science and Technology Program of Zhejiang Province, a Grant (2020ZDYF10 to QRF) from the Key R&D Program of Lishui City, and a Grant (LY21H160010 to YY) from the Basic Public Welfare Research Program of Zhejiang.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, China

    Xinhua Liu

  2. Zhejiang Provincial Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, School of Medicine, Lishui Hospital of Zhejiang University, Lishui, 323000, Zhejiang, China

    Rongfang Qiu, Min Xu, Miaomiao Meng, Siyu Zhao, Jiansong Ji & Yang Yang

  3. Department of Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, China

    Rongfang Qiu, Min Xu, Miaomiao Meng, Siyu Zhao, Jiansong Ji & Yang Yang

  4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Xinhua Liu, Rongfang Qiu & Yang Yang

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  1. Xinhua Liu
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  2. Rongfang Qiu
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  3. Min Xu
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  4. Miaomiao Meng
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Contributions

JJS and YY proposed and designed the study. YY and LXH wrote the manuscript. LXH conducted the bioinformatics analysis. QRF, LXH, XM, MMM, and ZSY performed the experiments.

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Correspondence to Jiansong Ji or Yang Yang.

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Liu, X., Qiu, R., Xu, M. et al. KMT2C is a potential biomarker of prognosis and chemotherapy sensitivity in breast cancer. Breast Cancer Res Treat 189, 347–361 (2021). https://doi.org/10.1007/s10549-021-06325-1

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