br Introduction br Breast cancer is
Breast cancer is the most common cancer among women worldwide  and is triggered by several risk factors. Its occurrence and devel-opment are multi-factorial and hormonal-dependent processes. The availability of sophisticated high-throughput technology, together with
well-developed bioinformatics tools, has significantly accelerated our understanding of the molecular basis of cancer. Currently, gene ex-pression profiles are being used to support cancer treatment decisions [2,3]. Cancer is a genetic disease, accompanied by gene mutations or ab-normal expression patterns. However, in recent years, increasing
Abbreviations: ER, estrogen receptor; PR, progesterone receptor; HR, hormonal receptor; HER2, human epidermal growth factor receptor 2; HR+/HER2-, HR positive and HER2 negative; HR-/HER2+, HR negative and HER2 positive; HR+/HER2+, HR positive and HER2 positive; AR, androgen receptor; IDC, infiltrating ductal carcinoma; ILC, infiltrating lobular carcinoma; FISH, fluorescence in situ hybridization; NGS, next generation sequencing; OS, overall survival; GDPH, Guangdong Provincial People's Hospital; TCGA, The Cancer Genome Atlas; METABRIC, Molecular Taxonomy of Breast Cancer International Consortium; PH, pro-portional hazard; KMT2C, Lysine Methyltransferase 2C; MLL3, Myeloid/lymphoid or mixed-lineage leukemia protein 3; MT, mutant; WT, wild-type; NA, not ap-plicable
Corresponding author at: Department of Breast Cancer, Guangdong provincal people’s Hospital & Guangdong, Academy of Medical Sciences, Guangzhou, China.
E-mail address: [email protected] (N. Liao).
1 These authors contributed equally to this work.
evidence has showed that epigenetic alterations can also change gene expression, which might be another cause for tumor occurrence and development . Furthermore, epigenetic mechanisms are involved in tumorigenesis. Epigenetic alterations, including RNA modification, non-coding RNA regulation, DNA modification, histone modification, and Filipin Complex remodeling, are characterized by heritability and re-versibility. Based on epigenetic alteration reversibility, epigenetic therapy, defined as the use of drugs or other epigenome-influencing techniques to treat medical conditions, is expected to be a promising approach to improve cancer prognosis .
Histone methylation is a type of epigenetic modification in the process of gene expression. A recent study indicated that histone lysine methyltransferases (KMTs), as important regulators of epigenetics, can be attractive drug targets for cancer therapy . KMTs are involved in the methylation of different histone amino acid sites catalyzed by his-tone methyltransferases, which changes the structure of chromatin and affects the transcription process of target genes [7–9]. Since the de-velopment of next-generation sequencing (NGS) techniques and the establishment of databases, it has now become possible to discover the role of histone modification in diverse human cancers.
KMT2C, located on chromosome 7q36, is a very large coding gene (1700 kb), also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3), and a member of the myeloid/lymphoid or mixed-lineage leukemia family. It encodes a nuclear protein with an AT hook DNA-binding domain, DHHC-type zinc finger, six PHD-type zinc fin-gers, SET domain, post-SET domain, and RING-type zinc finger (pro-vided by RefSeq, Jul 2008). KMT2C has been reported to be frequently mutated in multiple human cancers and is crucial for the occurrence and development of most cancers . However, the role of KMT2C in patients with breast cancer and the relationship between KMT2C mu-tation and clinicopathological characteristics in patients with breast cancer are unclear [10–16]. Therefore, the aim of this study was to evaluate the relationship between KMT2C mutation and clin-icopathological characteristics in breast cancer.
2. Material and methods
2.1. Patients and samples
This study was strictly carried out in accordance with the principles of the Declaration of Helsinki  and was approved by the ethics committee of Guangdong Provincial People's Hospital (GDPH) [2017312 H(RE)]. For the GDPH cohort, 411 patients with breast cancer from the GDPH (June 1, 2017 to September 27, 2018) were included in this study. The inclusion criteria for patients in this study were as follows: (1) diagnosed with invasive breast cancer, (2) qualified primary tumor tissue sequencing information, (3) complete clin-icopathological characteristic information, and (4) complete clinical information [sex, age of onset, menstrual status, primary tumor size, axillary lymph node status, distant metastasis status, pathological type, histological grading, molecular type, estrogen receptor (ER), proges-terone receptor, human epidermal growth factor receptor 2 (HER2), proliferating nuclear antigen, androgen receptor, and TNM stage]. Tumor tissue samples from these patients were collected and subjected to NGS.