Inactivation of Epigenetic Regulators due to Mutations in Solid Tumors

Немцова, М. В.; Mikhaylenko, Dmitry S.; Kuznetsova, Ekaterina; Быков, И И; Zamyatnin, Andrey A.

doi:10.1134/s0006297920070020

Cited by 3 publications

(1 citation statement)

References 91 publications

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“…Application of NGS allowed identification of tumors without mutations in the known cancer driver genes that are, however, characterized by mutations in genes encoding epigenetic factors and chromatin-modifying enzymes. Today, deregulation of epigenetic mechanisms in different types of tumors has been confirmed, but its causes are insufficiently studied [4,5].…”

Section: Introductionmentioning

confidence: 99%

Mutations in Epigenetic Regulation Genes in Gastric Cancer

Немцова

Калинкин

Kuznetsova

et al. 2021

Cancers

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We have performed mutational profiling of 25 genes involved in epigenetic processes on 135 gastric cancer (GC) samples. In total, we identified 79 somatic mutations in 49/135 (36%) samples. The minority (n = 8) of mutations was identified in DNA methylation/demethylation genes, while the majority (n = 41), in histone modifier genes, among which mutations were most commonly found in KMT2D and KMT2C. Somatic mutations in KMT2D, KMT2C, ARID1A and CHD7 were mutually exclusive (p = 0.038). Mutations in ARID1A were associated with distant metastases (p = 0.03). The overall survival of patients in the group with metastases and in the group with tumors with signet ring cells was significantly reduced in the presence of mutations in epigenetic regulation genes (p = 0.036 and p = 0.041, respectively). Separately, somatic mutations in chromatin remodeling genes correlate with low survival rate of patients without distant metastasis (p = 0.045) and in the presence of signet ring cells (p = 0.0014). Our results suggest that mutations in epigenetic regulation genes may be valuable clinical markers and deserve further exploration in independent cohorts.

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Section: Introductionmentioning

confidence: 99%

Mutations in Epigenetic Regulation Genes in Gastric Cancer

Немцова

Калинкин

Kuznetsova

et al. 2021

Cancers

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Short-chain fatty acids in cancer pathogenesis

Feitelson

Arzumanyan

Medhat

et al. 2023

Cancer Metastasis Rev

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Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of “health,” is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a “leaky gut,” permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.

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<i>LINE-1</i> hypomethylation and <i>HIST1H4F</i> hypermethylation as oncomarkers in liquid biopsy of colorectal cancer

Kondratova,

Botezatu,

Stroganova

et al. 2024

Usp. mol. onkol

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Introduction. Local hypermethylation of gene promoters and global genome hypomethylation are well-known manifestations of aberrant methylation associated with carcinogenesis. We investigated this phenomenon as a possible diagnostic marker for liquid biopsy of colorectal cancer using the original quantitative DNA melting analysis with hybridiza-tion probes (qDMA-HP) method. Aim. To quantify the methylation of HIST1H4F promoter and LINE-1 transposon in circulating blood plasma DNA of colorectal cancer patients. Materials and methods. Bisulfite-treated DNA samples isolated from blood plasma of healthy donors and cancer patients were analyzed. HIST1H4F methylation was assessed by asymmetric polymerase chain reaction with hybridized probe and post-amplification melting of probe / amplicon hybrids. To test for repetitive and highly polymorphic LINE-1 sequences, asymmetric polymerase chain reaction with hybridized probe and SYBR Green intercalating dye was used, followed by melting of hybrids and analysis of multicomponent melt curves. Results. High diagnostic efficiency of LINE-1 and HIST1H4F methylation markers in liquid biopsy of colorectal cancer was demonstrated with the area under the ROC curve = 0.92, sensitivity – 100 %, specificity – 84 %. Cross validation supports this result. Hypermethylation of HIST1H4F and hypomethylation of LINE-1 are statistically significantly correlated (Spearman correlation coefficient r = 0.4; p = 0.01). Conclusion. The qDMA-HP is suitable for quantitative assessment of aberrant methylation of various clinically significant genes.

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Inactivation of Epigenetic Regulators due to Mutations in Solid Tumors

Cited by 3 publications

References 91 publications

Mutations in Epigenetic Regulation Genes in Gastric Cancer

Mutations in Epigenetic Regulation Genes in Gastric Cancer

Short-chain fatty acids in cancer pathogenesis

<i>LINE-1</i> hypomethylation and <i>HIST1H4F</i> hypermethylation as oncomarkers in liquid biopsy of colorectal cancer

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