Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Tomičić, Maja; Dawood, Mona; Efferth, Thomas

doi:10.3390/cancers13164072

Cited by 13 publications

(4 citation statements)

References 109 publications

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“…Tumors whose methylation status was intermediate were more linked to post‐progression survival than hypermethylated ones. One possible explanation is that the presence of hypermethylated promoters and a probable lower expression of MGMT favors the accumulation of other DNA lesions that could confer a worse prognosis compared to the group of lesions classified as “intermediate methylation.” As an example, it has been shown that epigenetic inactivation of the MGMT gene can facilitate the appearance of mutations in TP53 and other genes implicated in the process of tumorigenesis or disease progression, 19,20 even though this may be again influenced by other factors such as the limited size of our study group.…”

Section: Discussionmentioning

confidence: 94%

Quantitative analysis of MGMT promoter methylation status changes by pyrosequencing in recurrent glioblastoma

et al. 2022

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BackgroundMGMT promoter methylation status can change in response to several factors, including treatment with alkylating agents. Some authors have attempted to quantify these alterations with inconsistent results.This study aims to determine changes in MGMT promoter methylation status by pyrosequencing, which quantitatively yields results, providing percentages of methylation of a given CpG dinucleotide in a cohort of patients reoperated for recurrent glioblastoma and having previously completed the Stupp protocol. MethodsA total of 25 pairs of glioblastoma preselected tumor samples were retrospectively analyzed using conventional DNA extraction techniques, bisul te conversion, and PCR ampli cation of the MGMT promoter gene. Methylation status was obtained using pyrosequencing of 4 CpG dinucleotides within the enhancer region of the MGMT promoter gene and depicted as percentages or categories (hypermethylated, intermediate methylation, unmethylated). Matched samples were compared using Wilcoxon signed-rank test, and the log-rank test was employed to establish a correlation between survival data and methylation status. ResultsMedian value of MGMT promoter methylation status declined after adjuvant treatment from 22.25-16.15%. (p = 0.872). A correlation without statistical signi cance between methylation in primary samples and OS was found (p = 0.102). Lower degrees of association were obtained when studying primary methylation and PFS (p = 0.187). Intermediate methylation status at recurrence was more linked to PPS (p = 0.03) ConclusionsSwitching in both directions was observed when analyzing methylation status as a continuous variable. These data suggest that the dynamics of epigenetics may be very complex and not entirely explained by clonal selection or tumor heterogeneity. BackgroundGene expression can be controlled by promoter regions located in close vicinity to sites where transcription of DNA into RNA begins. Some of these genomic areas are characterized by clusters of cytosine and guanine dinucleotides, called CpG islands. It is well known that hypermethylation of these

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Section: Discussionmentioning

confidence: 94%

Quantitative analysis of MGMT promoter methylation status changes by pyrosequencing in recurrent glioblastoma

et al. 2022

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“…The activation of oncogenes and inhibition of tumor suppressor genes lead to tumor growth and progression [52,53]. There is ample evidence that oncogenic kinases and tumor suppressors do not only contribute to drug resistance but also to cancer progression and worse outcomes for patients [54][55][56][57][58]. Thus, we investigated the prognostic value of the five top inhibited kinases for the overall survival time of human tumors.…”

Section: Discussionmentioning

confidence: 99%

Kinome-Wide Profiling Identifies Human WNK3 as a Target of Cajanin Stilbene Acid from Cajanus cajan (L.) Millsp.

Özenver

Kadioglu

et al. 2022

IJMS

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Pigeon Pea (Cajanus cajan (L.) Millsp.) is a common food crop used in many parts of the world for nutritional purposes. One of its chemical constituents is cajanin stilbene acid (CSA), which exerts anticancer activity in vitro and in vivo. In an effort to identify molecular targets of CSA, we performed a kinome-wide approach based on the measurement of the enzymatic activities of 252 human kinases. The serine-threonine kinase WNK3 (also known as protein kinase lysine-deficient 3) was identified as the most promising target of CSA with the strongest enzymatic activity inhibition in vitro and the highest binding affinity in molecular docking in silico. The lowest binding affinity and the predicted binding constant pKi of CSA (−9.65 kcal/mol and 0.084 µM) were comparable or even better than those of the known WNK3 inhibitor PP-121 (−9.42 kcal/mol and 0.123 µM). The statistically significant association between WNK3 mRNA expression and cellular responsiveness to several clinically established anticancer drugs in a panel of 60 tumor cell lines and the prognostic value of WNK3 mRNA expression in sarcoma biopsies for the survival time of 230 patients can be taken as clues that CSA-based inhibition of WNK3 may improve treatment outcomes of cancer patients and that CSA may serve as a valuable supplement to the currently used combination therapy protocols in oncology.

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“…Immune cell infiltration is important for tumor progression; however, it is an underrated factor for evaluating the efficacy of ICI treatment ( 29 ). Increasing evidence has shown that the interaction between tumors and the microenvironment is critical for the progression of CRC and effectiveness of immunotherapy ( 30 ). Therefore, we assessed the relative proportions of 22 immune cells in the high- and low-risk subgroups of CRC samples, including immune cell infiltration and immune function scores and the roles of various immune cells to explain the low response to ICI in patients with CRC.…”

Section: Discussionmentioning

confidence: 99%

Immune-related gene-based prognostic index for predicting survival and immunotherapy outcomes in colorectal carcinoma

Liang

Sun

et al. 2022

Front. Immunol.

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IntroductionColorectal cancer shows high incidence and mortality rates. Immune checkpoint blockade can be used to treat colorectal carcinoma (CRC); however, it shows limited effectiveness in most patients.MethodsTo identify patients who may benefit from immunotherapy using immune checkpoint inhibitors, we constructed an immune-related gene prognostic index (IRGPI) for predicting the efficacy of immunotherapy in patients with CRC. Transcriptome datasets and clinical information of patients with CRC were used to identify differential immune-related genes between tumor and para-carcinoma tissue. Using weighted correlation network analysis and Cox regression analysis, the IRGPI was constructed, and Kaplan–Meier analysis was used to evaluate its predictive ability. We also analyzed the molecular and immune characteristics between IRGPI high-and low-risk subgroups, performed sensitivity analysis of ICI treatment, and constructed overall survival-related receiver operating characteristic curves to validate the IRGPI. Finally, IRGPI genes and tumor immune cell infiltration in CRC model mice with orthotopic metastases were analyzed to verify the results.ResultsThe IRGPI was constructed based on the following 11 hub genes: ADIPOQ, CD36, CCL24, INHBE, UCN, IL1RL2, TRIM58, RBCK1, MC1R, PPARGC1A, and LGALS2. Patients with CRC in the high-risk subgroup showed longer overall survival than those in the low-risk subgroup, which was confirmed by GEO database. Clinicopathological features associated with cancer progression significantly differed between the high- and low-risk subgroups. Furthermore, Kaplan–Meier analysis of immune infiltration showed that the increased infiltration of naïve B cells, macrophages M1, and regulatory T cells and reduced infiltration of resting dendritic cells and mast cells led to a worse overall survival in patients with CRC. The ORC curves revealed that IRGPI predicted patient survival more sensitive than the published tumor immune dysfunction and rejection and tumor inflammatory signatureDiscussionThus, the low-risk subgroup is more likely to benefit from ICIs than the high-risk subgroup. CRC model mice showed higher proportions of Tregs, M1 macrophages, M2 macrophages and lower proportions of B cells, memory B cell immune cell infiltration, which is consistent with the IRGPI results. The IRGPI can predict the prognosis of patients with CRC, reflect the CRC immune microenvironment, and distinguish patients who are likely to benefit from ICI therapy.

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Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Cited by 13 publications

References 109 publications

Quantitative analysis of MGMT promoter methylation status changes by pyrosequencing in recurrent glioblastoma

Quantitative analysis of MGMT promoter methylation status changes by pyrosequencing in recurrent glioblastoma

Kinome-Wide Profiling Identifies Human WNK3 as a Target of Cajanin Stilbene Acid from Cajanus cajan (L.) Millsp.

Immune-related gene-based prognostic index for predicting survival and immunotherapy outcomes in colorectal carcinoma

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