scholarly journals Landscape Of HOXA Genes Methylation in Colorectal Cancer

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Muhiddin Ishak ◽  
Rashidah Baharudin ◽  
Loh Teng-Hern Tan ◽  
Learn-Han Lee ◽  
Nurul-Syakima Ab Mutalib
Keyword(s):  
Colorectal Cancer ◽  
Cancer Susceptibility ◽  
Cpg Islands ◽  
Methylation Pattern ◽  
Gene Promoters ◽  
Normal Tissues ◽  
Genes Encoding ◽  
Hoxa Genes ◽  
A Minor ◽  
Hoxa Gene

Colorectal cancer (CRC) is among the most common cancers worldwide and the second leading cause of cancer-related death in Malaysia. The HOXA gene cluster is a family of Homeobox A genes encoding transcriptional regulators that play vital roles in cancer susceptibility and progression. Dysregulated HOXA expression influences various aspects of carcinogenesis processes. Therefore, this study aims to elucidate the methylation landscape of HOXA genes in CRC. Twelve pairs of CRC — adjacent normal tissues were subjected to Infinium DNA MethyEPIC array. Differentially methylatedregions were identified using the ChAMP Bioconductor and methylation levels of HOXA genes were manually curated. We identified 100 significantly differentially methylated probes annotated to HOXA genes. HOXA3 has the highest number of differentially methylated probes (n=27), followed by HOXA2 (n=20) and HOXA4 (n=14). The majority (43%) of the probes were located at the transcription start site (TSS) 200, which is one of the gene promoters. In respect to CpG islands (CGI), the probes were equally located in the island and shore regions (47% each) while a minor percentage was in the shelf (6%). Our work gave a comprehensive assessment of the DNA methylation pattern of HOXA genes and provide the first evidence of HOXA2, HOXA3 and HOXA4 differential methylation in Malaysian CRC. The new knowledge from this study can be utilized to further increase our understanding of CRC methylomics, particularly on the homeobox A genes. The prognostic and diagnostic roles of the differentially methylated HOXA genes warrant future investigations.

scholarly journals Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures

2019 ◽  
Vol 116 (48) ◽  
pp. 24285-24295 ◽  
Author(s):  
Iradj Sobhani ◽  
Emma Bergsten ◽  
Séverine Couffin ◽  
Aurélien Amiot ◽  
Biba Nebbad ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Bacterial Species ◽  
Aberrant Crypt Foci ◽  
Sporadic Colorectal Cancer ◽  
Gene Promoters ◽  
Normal Tissues ◽  
Complex Interactions ◽  
Dna Alterations ◽  
Methylation Patterns ◽  
Epigenetic Signatures

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls’ microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.

scholarly journals Methylation analysis of MIR200 family in Mexican patients with colorectal cancer

2019 ◽  
Vol 68 (3) ◽  
pp. 782-785
Author(s):  
Carlos Rogelio Alvizo-Rodriguez ◽  
Maria de la Luz Ayala-Madrigal ◽  
Jesus Arturo Hernandez-Sandoval ◽  
Helen Haydee Fernanda Ramirez-Plascencia ◽  
Christian Octavio Gonzalez-Villaseñor ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Peripheral Blood ◽  
Reference Group ◽  
Polyacrylamide Gel Electrophoresis ◽  
Methylation Pattern ◽  
Methylation Analysis ◽  
Blood Samples ◽  
Normal Tissues ◽  
Negative Results ◽  
Specific Pcr

The present study aimed to analyze the methylation pattern of the MIR200 family in the colorectal tissues and peripheral blood of colorectal cancer (CRC) patients. Previous informed consent, 102 samples of colorectal tissues (tumor and adjacent normal tissues) and 40 peripheral blood samples were collected from CRC patients. Additionally, we included a reference group of 40 blood samples. DNA extraction was done for colorectal tissues and peripheral blood. For methylation-specific PCR, we used bisulfite-treated DNA and controls for methylated and unmethylated DNA were included to each assay. PCR fragments were separated by 6% polyacrylamide gel electrophoresis. Methylation-positive and methylation-negative results were confirmed by bisulfite genomic sequencing technique. We analyzed 102 colorectal tissues and 40 blood samples from 51 CRC patients. MIR200B/MIR200A/MIR429 methylation analysis discloses no differences among tissues (p>0.05). However, MIR200C/MIR141 methylation showed differences between colorectal tissues and peripheral blood of CRC patients (p<0.0001) and mainly methylated alleles were observed in peripheral blood. These findings suggest a tissue-specific methylation pattern for the MIR200C/MIR141 promoter.

scholarly journals Methylation Degrees of NIS and TIMP-3 Promoters in Well-Differentiated Thyroid Tumors

2020 ◽  
Author(s):  
Noman Arab ◽  
Maryam Zarkesh ◽  
Zahra Nozhat ◽  
Sara Sheikholeslami ◽  
Marziyeh Salehi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Thyroid Cancer ◽  
Cpg Islands ◽  
Cross Sectional Study ◽  
Methylation Pattern ◽  
Mrna Levels ◽  
Cross Sectional ◽  
Normal Tissues ◽  
Well Differentiated ◽  
Promoter Dna

Abstract Background The aim of this study was to investigate the DNA methylation pattern in CpG islands of NIS and TIMP-3 promoters in thyroid cancers and the matched non-tumoral tissues as well as multinodular goiter (MNG) tissues. This cross-sectional study was performed on total 64 patients including 28 papillary thyroid cancer (PTC), 9 follicular thyroid cancer (FTC) and 27 MNG cases. Method: The bisulfite sequencing PCR technique was used to evaluate the promoter methylation pattern of the NIS and TIMP-3 genes. Results NIS mRNA levels were decreased in both of PTC and FTC tumoral tissues compared to their adjacent normal tissues (P = 0.04 and P = 0.03, respectively). TIMP-3 expression was also reduced in both PTC and FTC tumoral tissues compared to the adjacent non-tumoral tissues (P = 0.02 and P = 0.03, respectively). Moreover, a significant reduction in TIMP-3 expression was observed in FTC tissues compared to the MNG samples (P = 0.05). The methylation on NIS promoter was not a common event in PTC samples, but it was frequent in FTC (P < 0.05). A significant hyper-methylation was shown in TIMP-3 promoter in both PTC and FTC tissues compared to the non-tumoral and MNG samples (P < 0.05). Conclusion Aberrant promoter DNA methylation suggests potential utility to differentiate benign and malignant PTC and FTC tissues for early diagnosis, and contribution for personalized clinical management and surveillance. According to the reversibility of DNA methylation, these events may be potential targets for demethylating treatments.

scholarly journals Epigenetic Inactivation of Protocadherin 10 by Methylation in Colorectal Cancer

2020 ◽  
Author(s):  
Mohammad Amin Kerachian ◽  
Sahar Tavakolian ◽  
Matineh Barati Bagherabad ◽  
Dor Mohammad Kordi-Tamandani ◽  
Mohammad Reza Abbaszadegan
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Cpg Islands ◽  
High Specificity ◽  
Suppressor Gene ◽  
Potential Candidate ◽  
Critical Function ◽  
Normal Tissues

Aberrant promoter methylation of CpG islands of tumor-suppressor genes has been recognized as one of the important tumor markers for cancer detection. The aim of this study was to investigate the promoter methylation status of protocadherin 10 (PCDH10), a tumor suppressor gene, in Iranian colorectal cancer (CRC) patients. Cancerous and the adjacent normal tissues obtained from 38 CRC patients were used to assess the methylation status of PCDH10 with Methylation Specific PCR, in addition, to study the expression level of this gene by quantitative PCR. The relationship between hypermethylation and the demographic characteristics of these patients was analyzed. The promoter methylation level of PCDH10 was statistically different between tumoral and normal tissues in CRC patients. Twenty-seven out of 38 patients showed hypermethylation with a sensitivity of 73% and a specificity of 97%. PCDH10 expression decreased in 15 cases (46%) as 16 cases (50 %) showed overexpression and 1 case (4%) had no changes. Not a significant association was reported between PCDH10 hypermethylation and the clinicopathological characteristics (P>0.05). Our results indicated that PCDH10 methylation has a critical function in CRC, with a nearly elevated sensitivity and a high specificity in the Iranian population, qualify it as a potential candidate biomarker. © 2019 Tehran University of Medical Sciences. All rights reserved. Acta Med Iran 2019;57(8):472-477.

scholarly journals Epigenome-Wide DNA Methylation Profiling in Colorectal Cancer and Normal Adjacent Colon Using Infinium Human Methylation 450K

Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 198
Author(s):  
Rashidah Baharudin ◽  
Muhiddin Ishak ◽  
Azliana Muhamad Yusof ◽  
Sazuita Saidin ◽  
Saiful Effendi Syafruddin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Cpg Islands ◽  
R Package ◽  
Integrated Analysis ◽  
Normal Tissues ◽  
Open Sea ◽  
Aberrant Dna Methylation ◽  
Methylation Profiling ◽  
Hypermethylated Genes

The aims were to profile the DNA methylation in colorectal cancer (CRC) and to explore cancer-specific methylation biomarkers. Fifty-four pairs of CRCs and the adjacent normal tissues were subjected to Infinium Human Methylation 450K assay and analysed using ChAMP R package. A total of 26,093 differentially methylated probes were identified, which represent 6156 genes; 650 probes were hypermethylated, and 25,443 were hypomethylated. Hypermethylated sites were common in CpG islands, while hypomethylated sites were in open sea. Most of the hypermethylated genes were associated with pathways in cancer, while the hypomethylated genes were involved in the PI3K-AKT signalling pathway. Among the identified differentially methylated probes, we found evidence of four potential probes in CRCs versus adjacent normal; HOXA2 cg06786372, OPLAH cg17301223, cg15638338, and TRIM31 cg02583465 that could serve as a new biomarker in CRC since these probes were aberrantly methylated in CRC as well as involved in the progression of CRC. Furthermore, we revealed the potential of promoter methylation ADHFE1 cg18065361 in differentiating the CRC from normal colonic tissue from the integrated analysis. In conclusion, aberrant DNA methylation is significantly involved in CRC pathogenesis and is associated with gene silencing. This study reports several potential important methylated genes in CRC and, therefore, merit further validation as novel candidate biomarker genes in CRC.

scholarly journals Epigenetic profiling of MUTYH, KLF6, WNT1 and KLF4 genes in carcinogenesis and tumorigenesis of colorectal cancer

BioMedicine ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 22 ◽  
Author(s):  
Kosar Babaei ◽  
Roya Khaksar ◽  
Tahereh Zeinali ◽  
Hossein Hemmati ◽  
Ahmadreza Bandegi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Dna Methylation ◽  
Cpg Islands ◽  
Methylation Pattern ◽  
Tumor Initiation ◽  
Promoter Regions ◽  
Rna Remodeling ◽  
New Biomarkers ◽  
Gene Expression Levels

Colorectal cancer (CRC) is distinguished by epigenetic elements like DNA methylation, histone modification, histone acetylation and RNA remodeling which is related with genomic instability and tumor initiation. Correspondingly, as a main epigenetic regulation, DNA methylation has an impressive ability in order to be used in CRC targeted therapy. Meaningly, DNA methylation is identified as one of most important epigenetic regulators in gene expression and is considered as a notable potential driver in tumorigenesis and carcinogenesis through gene-silencing of tumor suppressors genes. Abnormal methylation situation, even in the level of promoter regions, does not essentially change the gene expression levels, particularly if the gene was become silenced, leaving the mechanisms of methylation without any response. According to the methylation situation which has a strong eagerness to be highly altered on CpG islands in carcinogenesis and tumorigenesis, considering its epigenetic fluctuations in finding new biomarkers is of great importance. Modifications in DNA methylation pattern and also enrichment of methylated histone signs in the promoter regions of some certain genes like MUTYH, KLF4/6 and WNT1 in different signaling pathways could be a notable key contributors to the upregulation of tumor initiation in CRC. These epigenetic alterations could be employed as a practical diagnostic biomarkers for colorectal cancer. In this review, we will be discuss these fluctuations of MUTYH, KLF4/6 and WNT1 genes in CRC.

scholarly journals De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

2019 ◽  
Author(s):  
Roza H. Ali Masalmeh ◽  
Cristina Rubio-Ramon ◽  
Francesca Taglini ◽  
Jonathan Higham ◽  
Hazel Davidson-Smith ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Cpg Islands ◽  
Dna Methyltransferases ◽  
Transcriptional Elongation ◽  
Normal Tissues ◽  
Colorectal Cancer Cells ◽  
Low Levels ◽  
Colorectal Tumours

AbstractThe aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such as MLH1. Current models propose that these CGIs are targeted by de novo DNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels of de novo DNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that instead de novo DNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting that de novo DNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.

scholarly journals Global Methylome Scores Correlate with Histological Subtypes of Colorectal Carcinoma and Show Different Associations with Common Clinical and Molecular Features

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5165
Author(s):  
María del Carmen Turpín-Sevilla ◽  
Fernando Pérez-Sanz ◽  
José García-Solano ◽  
Patricia Sebastián-León ◽  
Javier Trujillo-Santos ◽  
...  
Keyword(s):  
Cpg Island ◽  
Cpg Islands ◽  
Promoter Hypermethylation ◽  
Methylation Pattern ◽  
Asymmetric Distribution ◽  
Gene Promoters ◽  
Histological Subtypes ◽  
Promoter Regions ◽  
Global Methylation ◽  
Molecular Features

Background. The typical methylation patterns associated with cancer are hypermethylation at gene promoters and global genome hypomethylation. Aberrant CpG island hypermethylation at promoter regions and global genome hypomethylation have not been associated with histological colorectal carcinomas (CRC) subsets. Using Illumina’s 450 k Infinium Human Methylation beadchip, the methylome of 82 CRCs were analyzed, comprising different histological subtypes: 40 serrated adenocarcinomas (SAC), 32 conventional carcinomas (CC) and 10 CRCs showing histological and molecular features of microsatellite instability (hmMSI-H), and, additionally, 35 normal adjacent mucosae. Scores reflecting the overall methylation at 250 bp, 1 kb and 2 kb from the transcription starting site (TSS) were studied. Results. SAC has an intermediate methylation pattern between CC and hmMSI-H for the three genome locations. In addition, the shift from promoter hypermethylation to genomic hypomethylation occurs at a small sequence between 250 bp and 1 Kb from the gene TSS, and an asymmetric distribution of methylation was observed between both sides of the CpG islands (N vs. S shores). Conclusion. These findings show that different histological subtypes of CRC have a particular global methylation pattern depending on sequence distance to TSS and highlight the so far underestimated importance of CpGs aberrantly hypomethylated in the clinical phenotype of CRCs.

scholarly journals Colorectal Cancer Early Detection in Stool Samples Tracing CpG Islands Methylation Alterations Affecting Gene Expression

2020 ◽  
Vol 21 (12) ◽  
pp. 4494
Author(s):  
Ana Florencia Vega-Benedetti ◽  
Eleonora Loi ◽  
Loredana Moi ◽  
Sandra Orrù ◽  
Pina Ziranu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Cell Signalling ◽  
Cpg Islands ◽  
Digital Pcr ◽  
Protein Levels ◽  
Normal Tissues ◽  
Non Invasive ◽  
Cancer Early Detection ◽  
Stool Samples

Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC.

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