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  • br TCGA Cohort br METABRIC Cohort br GDPH

    2020-08-14


    TCGA Cohort
    METABRIC Cohort
    GDPH Cohort
    WT KMT2C MT KMT2C
    WT KMT2C MT KMT2C
    WT KMT2C MT KMT2C
    Premenopausal
    NA
    YES
    Ductal
    NA
    Histologic grade
    I
    II
    III
    NA
    Positive
    Positive
    Positive
    Positive
    NA
    NA
    AR
    Positive
    Negative
    NA
    Fig. 3. Kaplan-Meier survival curves based on KMT2C mutation status. (A) Overall patients in TCGA cohort; (B) Overall patients in METABRIC cohort; (C) HR + breast cancer patients in TCGA cohort; (C) HR + breast cancer patients in METABRIC cohort.
    modification is one of the signs of aging. Labarge et al. [24] showed that aging of breast sybr安全dna凝胶染料 can change the structure of the breast mi-croenvironment. The aging process is associated with changes in the breast tissue that not only disrupt the tumor suppressive activity of normal tissue but also enhance age-related epigenetic changes. These findings can potentially explain our results. Interestingly, Labarge et al. [24] found that the epigenetic modification status can be changed through diet, exercise, nutrition, or other factors, indicating that epi-genetic changes are preventable. Our study provides a preliminary basis for studies on the primary prevention of breast cancer in elderly pa-tients in the future. Additionally, KMT2C mutations were found at a significantly higher frequency in patients with HR+/HER2- breast cancer in the three cohorts. In accordance with the findings of a pre-vious study [25], the H3K4 methyltransferase KMT2C is required for hormone-driven ER activity and breast cancer proliferation. KMT2C knockdown inhibited estrogen-dependent gene expression, which would likely mediate the occurrence of estrogen-dependent breast cancer by regulating activity of ER. The present study also demon-strated that KMT2C is one of the most commonly mutated genes in ER-positive breast cancer. However, whether the relatively higher pro-portion of KMT2C mutations in HR+/HER2- breast cancer can con-tribute to disease treatment in Chinese patients merits further in-vestigation. Furthermore, the KMT2C mutation rate in patients with ILC of the GDPH (30%) cohort was significantly higher than that reported for Western populations (5–8%) [26–28]. Previous studies have shown that CDH1 is the most common mutated gene in patients with ILC breast cancer in Western populations (50–65% vs. 4–8% in Asian populations) [29,30]. Racial diversity has been shown to be intimately associated with the pathogenesis of cancer [31,32]. However, the mutational genomic profiles of ILC in Asian breast cancer patients have not been explored in any detail. Therefore, determining whether KMT2C is the main susceptibility gene of Asian patients with ILC could be a point of interest for future research. r> Another significant question that should be addressed is whether KMT2C mutations are related to prognosis. KMT2C heterozygous 
    mutations might also be associated with heritability driven events [33]. In addition, KMT2C is considered to act as a tumor suppressor and deletion of the KMT2C gene was shown to be associated with poor prognosis in acute myeloid leukemia [33]. Moreover, Sato et al. [13] downloaded and analyzed mRNA data of KMT2C for 401 patients with ER + breast cancer from cBioPortal for Cancer Genomics and found that patients with low expression of KMT2C had a worse prognosis. However, the results of the present study contradict this finding, sug-gesting that tumors harboring KMT2C mutations might not be an in-dependent risk factor in the prognosis of patients with breast cancer. Although previous studies have showed that KMT2C might play a role as a tumor suppressor gene in breast cancer, the results of TCGA and the METABRIC cohorts showed that KMT2C mutation was not associated with a poor prognosis. The reason for this discrepancy might be that the prognosis of patients with breast cancer is a complex and multifactorial process and that epigenetic modification is a reversible process with medications or dietary changes. Epigenetics is a rapidly growing and emerging field of cancer research. Further focus on this field will help to better understand the pathophysiology and molecular mechanisms that drive carcinogenesis. With the rapid development of NGS techniques and new drug discovery, the ease of use of such enzymes and gene regulators can provide new targets for the adjuvant treatment of can-cers. Recently, histone modification has emerged as a major element of chromatin function and gene expression, and its deregulation is related to cancer development. Unlike the diseases caused by DNA sequence changes, several epigenetic variations are reversible; accordingly, his-tone methyltransferase is an attractive target for biomedical research among histone-modified enzymes.