Cis-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases

Cruz, Miguel Ruiz-de la; Cruz-Montoya, Aldo de la; Jiménez, Ernesto Rojas; Gregorio, Héctor Martínez; Velásquez, Clara Estela Díaz; Vega, Jimena Paredes de la; Hernández-Hernández, Fidel de la Cruz; Paniagua, Felipe Vaca

doi:10.3390/cancers13194807

Cited by 10 publications

(13 citation statements)

References 155 publications

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“…When compared between NCKAP1 expression, tumor grade, TNM stage, and lymph node metastasis, a negative correlation was observed, suggesting that NCKAP1 may have an antitumor effect in ccRCC. Other studies have shown that transcriptional repression of tumor suppressor genes occurs with tumor progression due to hypermethylation of promoter regions ( Ruiz de la Cruz et al, 2021 ). Therefore, we speculated that low expression of NCAKP1 might be associated with high methylation levels in ccRCC, which is consistent with our previous results.…”

Section: Discussionmentioning

confidence: 99%

NCKAP1 is a Prognostic Biomarker for Inhibition of Cell Growth in Clear Cell Renal Cell Carcinoma

Chen

Zhang

et al. 2022

Front. Genet.

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Background: Clear cell renal cell carcinoma (ccRCC) is the most frequent type of kidney cancer. Nck-associated protein 1 (NCKAP1) is associated with poor prognosis and tumor progression in several cancer types, but the function and prognostic value of NCKAP1 in ccRCC remain poorly understood.Methods: Using the Ualcan database, we evaluated the correlation between NCKAP1 expression and clinical features of ccRCC. These data were validated by immunohistochemical staining for NCKAP1 in a cohort of ccRCC patients. We assessed the prognostic value of NCKAP1 using GEPIA2 survival analysis. NCKAP1 function was characterized in vitro and in vivo using NCKAP1-overexpression ACHN cell lines. The LinkedOmics and GSCALite databases were used to investigate identify potential NCKAP1-targeted medicines that may play a role in the treatment of ccRCC. The impact of NCKAP1 expression on immune infiltration was also evaluated.Results: NCKAP1 was significantly downregulated in ccRCC and correlated with advanced clinicopathological features and poor prognosis. Overexpression of NCKAP1 in ACHN cells reduced proliferation, invasion and migration capacity in vitro and inhibited tumor growth in vivo. According to the LinkedOmics, GSCALite and TIMER databases, NCKAP1 and related genes function primarily in ribosomal signaling, oxidative phosphorylation, TGF-β, and EMT-related signaling pathways. NCKAP1 was also shown to positively correlate with immune cell types, biomarkers, and immune checkpoints in ccRCCs.Conclusions: NCKAP1 may play a vital tumor-suppressive role in ccRCC and is potentially a useful prognostic biomarker.

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Section: Discussionmentioning

confidence: 99%

NCKAP1 is a Prognostic Biomarker for Inhibition of Cell Growth in Clear Cell Renal Cell Carcinoma

Chen

Zhang

et al. 2022

Front. Genet.

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“…These may include exposure to xenobiotic agents, alcohol, hormones, or reduced intake of DNA methylation precursors [56]. ii) High level, locus wide methylation in RAD51C, BRCA1, and POLH detected in three patients are product of noncoding genetic alterations in the neighboring regions, causing secondary cis epimutations [9,41,48]. Additional support for this hypothesis was reported recently by Takahashi et al (2023).…”

Section: Discussionmentioning

confidence: 65%

“…We propose that the hypermethylation of these promoters may be caused by neighboring mutations. This mechanism is known as cis secondary epimutation, and has been reported in colorectal cancer and other diseases [9,41,48]. Only one study of this phenomenon has been reported in HBOC patients, where an hypermethylated BRCA1 allele (>40% of promoted methylation) cosegregated with the variant c.-107A>T in the BRCA1 5'UTR [48].…”

Section: Discussionmentioning

confidence: 99%

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Peripheral blood DNA methylation analysis reveals epigenetic marks associated with hereditary breast and ovarian cancer risk

Paniagua,

Cruz,

Gregorio

et al. 2023

Preprint

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Background. Only a fraction of 15-20% of hereditary breast and ovarian cancer (HBOC) patients carry pathogenic coding genetic variants. Therefore, other pathogenic molecular mechanisms could explain the etiopathology of the syndrome. Aberrant germline DNA methylation in tumor suppressors has been reported in HBOC. Methods. We aimed to discover novel methylation marks associated with HBOC risk in 231 incident cases negative for pathogenic variants and 156 healthy controls using peripheral blood DNA, through methylation analysis by targeted bisulfite sequencing (NGS-Illumina) on 18 tumor suppressor gene promoters (330 CpG sites). Results. Increased methylation levels were detected in the promoters of EPCAM (p=0.00088), ATM (p=0.0074), and RAD51C (p=0.018). Four specific sites were linked to an increased risk of HBOC, FANCI (cg89786999) OR:1.64 (95%CI:1.3-2.0), PALB2 (cg23652916) OR=1.65 (95%CI:1.4-1.9), MSH2 (cg47630224) OR:1.93 (95%CI:1.5-2.4), and EPCAM (cg47596828) OR= 2.93 (95%CI:2.1-4.1). The biomarker capacity of the four sites showed an area under the curve (AUC) of 0.758, high specificity and sensitivity. Comparison with three well-established cohorts revealed that MSH2 cg47630224 methylation was associated with 3-fold increased HBOC risk (AUC: 0.892, sensitivity: 0.90, specificity: 0.89). Conclusions. Four novel DNA methylation CpG sites were associated with HBOC risk, suggesting potential application as biomarkers in patients without detectable coding mutations.

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“…Oral squamous cell carcinoma (OSCC) is the third most common cancer in developing countries and the sixth most common cancer globally [27]. Today, with the continuous development of molecular biology, it has been found that cancer was caused by genetic, metabolic, inflammatory, and epigenetic factors [28]. These lead to abnormal cell physiology and signal pathway conduction, which led to abnormal cell proliferation and differentiation, eventually developing into cancer [29].…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological Significance of AKT1 and PLK1 Expression in Oral Squamous Cell Carcinoma

Sun

Dong

et al. 2022

Disease Markers

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Purpose. Oral squamous cell carcinoma (OSCC) is the sixth leading cause of cancer-related death worldwide and is characterized by metastasis and recurrence. We aimed to evaluate the expression of AKT1 and PLK1 in OSCC and identify their correlation with the clinical and histological features and prognosis of patients with OSCC. Methods. Tissue samples were collected from 70 patients with OSCC and 50 patients with normal oral mucosa. The expression levels of AKT1 and PLK1 in OSCC tissues and normal oral mucosa were detected by immunohistochemistry. The chi-square test was used to identify correlations between the expression levels of AKT1 and PLK1 with patients’ clinicopathologic characteristics. Survival analysis was assessed by the Kaplan–Meier method. Spearman’s rank correlation test was used to determine the relationships between AKT1 and PLK1 expressions. The bioinformatics database GEPIA was used to verify the experimental results. Results. The chi-square test and Fisher’s exact test showed that the positive expression rate of AKT1 and PLK1 in OSCC tissue was significantly higher than that in the normal oral mucosa ( P < 0.05 ). PLK1 expression levels were significantly correlated with tumor stage and size ( P < 0.05 ). Kaplan–Meier analysis showed that the survival time of AKT1 and PLK1 with high expression was significantly shorter than that of patients with low expression ( P < 0.05 ). Spearman’s rank correlation test showed a strong correlation between AKT1 and PLK1 expression in OSCC tissue ( R = 0.53 ; P < 0.05 ). GEPIA bioinformatics database analysis results show that the expression and overall survival of AKT1 and PLK1 analysis and the correlation analysis of AKT1 and PLK1 were consistent with experimental results. Conclusion. AKT1 and PLK1 expressions are associated with the occurrence and progression of OSCC and may be used as diagnostic and prognostic indicators of OSCC. There may be a correlation between AKT1 and PLK1 in OSCC tissue.

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Cis-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases

Cited by 10 publications

References 155 publications

NCKAP1 is a Prognostic Biomarker for Inhibition of Cell Growth in Clear Cell Renal Cell Carcinoma

NCKAP1 is a Prognostic Biomarker for Inhibition of Cell Growth in Clear Cell Renal Cell Carcinoma

Peripheral blood DNA methylation analysis reveals epigenetic marks associated with hereditary breast and ovarian cancer risk

Clinicopathological Significance of AKT1 and PLK1 Expression in Oral Squamous Cell Carcinoma

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