Quantitative validation of GJC1 promoter hypermethylation in benign and malignant colorectal tumors

We have previously shown that the gap junction protein γ 1 (GJC1) gene, encoding the connexin-45 protein, is inactivated by promoter hypermethylation in colorectal cancer. This was confirmed in a recent Endocrine-Related Cancer publication analyzing a limited number of samples. The aim of this study was to analyze GJC1 in a larger clinical cohort (n=485) and to assess whether or not the promoter hypermethylation was associated with clinical or pathological features. The methylation of GJC1 was confirmed to be tumor specific and was observed in 33% of colorectal cancers and 12% of adenomas. The methylation was strongly associated with BRAF mutations (P=5.64×10−13) as well as with proximal tumor location (P=1.42×10−3), features compatible with a CpG island methylator phenotype.

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Lower LINE-1 methylation is associated with promoter hypermethylation and distinct molecular features in gastric cancer

Epigenomics ◽

10.2217/epi-2019-0091 ◽

2019 ◽

Vol 11 (15) ◽

pp. 1651-1659

Author(s):

Sayumi Tahara ◽

Tomomitsu Tahara ◽

Noriyuki Horiguchi ◽

Masaaki Okubo ◽

Tsuyoshi Terada ◽

...

Keyword(s):

Gastric Cancer ◽

Gastric Mucosa ◽

Cpg Island ◽

Methylation Status ◽

Promoter Hypermethylation ◽

Cpg Island Methylator Phenotype ◽

Line1 Methylation ◽

Methylator Phenotype ◽

H Pylori ◽

Mlh1 Methylation

Aim: To investigate the associations between LINE1 methylation, an indicator for genome-wide hypomethylation, molecular and clinicopathological characteristics of gastric cancer (GC) patients. Patients & methods: LINE1 methylation statuses were examined in paired cancerous, non-neoplastic mucosa from 217 GC and gastric mucosa from separate group of 224 noncancer patients. CpG island methylator phenotype, TP53 and KRAS mutation, MLH1 methylation status and promoter hypermethylation of GC related and H. pylori-related genes were examined. Results: Lower LINE1 methylation was observed in primary GC compared with non-neoplastic gastric mucosa and associated with CpG island methylator phenotype, TP53 mutation, MLH1 methylation and promoter hypermethylation of GC related and H. pylori-related genes. Conclusion: Lower LINE1 methylation correlates specific molecular subtypes and promoter hypermethylation in GC.

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The Methylation of SDC2 and TFPI2 Defined Three Methylator Phenotypes of Colorectal Cancer

10.21203/rs.3.rs-1022929/v1 ◽

2021 ◽

Author(s):

Ruixue Lei ◽

Yanteng Zhao ◽

Kai Huang ◽

Qian Wang ◽

Kangkang Wan ◽

...

Keyword(s):

Colorectal Cancer ◽

Cpg Island ◽

Methylation Status ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Tumor Location ◽

Functional Enrichment ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype ◽

Almost All

Abstract BackgroudMethylated SDC2 and TFPI2 are applied frequently for the early detection of colorectal cancer (CRC). However, they often miss some positive samples, which directly affects their sensitivities, and the underlining mechanism is not well known.Methods:CRC samples from TCGA and GEO datasets were divided into three groups, Highmethylation/ High-methylation (HH), High-methylation/Low-methylation (HL), and Lowmethylation/Low-methylation (LL) according to the methylation status of SDC2 and TFPI2 promoters. Variations in age, tumor location, and microsatellite instable were then assessed between the three groups and verified in our custom cohort.ResultsSamples of HL group preferred to derive from left-sided CRCs (P < 0.05). HH samples showed the highest microsatellite instability and mutation load (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02, P = 0.0055). Almost all mutations of BRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were observed in HH group (HH/HL/LL: 51/0/1, P = 0.018). Besides, older patients were frequently found in HH group. Expression analysis identified 37, 84, and 22 group-specific differentially expressed genes (DEGs) for HH, HL, and LL, respectively. Functional enrichment analysis revealed that HH-specific DEGs were mainly related to transcription regulation, while LL-specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration.Conclusions:The three methylation phenotypes identified based on SDC2 and TFPI2 methylation status showed extensive variations in tumor location, patient age, MSI and ECM biology processes, suggesting that these respective sides should be considered when developing new methylation-based biomarkers for CRC detection.

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CpG Island Methylator Phenotype in Colorectal Cancers: Comparison of the New and Classic CpG Island Methylator Phenotype Marker Panels

Archives of Pathology & Laboratory Medicine ◽

10.5858/2008-132-1657-cimpic ◽

2008 ◽

Vol 132 (10) ◽

pp. 1657-1665 ◽

Cited By ~ 1

Author(s):

Sun Lee ◽

Nam-Yun Cho ◽

Eun Joo Yoo ◽

Jung Ho Kim ◽

Gyeong Hoon Kang

Keyword(s):

Clinical Outcome ◽

Microsatellite Instability ◽

Braf Mutation ◽

Cpg Island ◽

Tumor Location ◽

Colorectal Cancers ◽

Clinicopathologic Features ◽

Cpg Island Methylator Phenotype ◽

P Values ◽

Methylator Phenotype

Abstract Context.—CpG island methylator phenotype (CIMP) designates a subset of colorectal cancers featuring concordant hypermethylation of multiple promoter CpG islands. Little is known about the clinical outcome or histologic characteristics of CIMP-positive colorectal cancers defined by recently identified CpG island methylator phenotype panels. Objective.—To investigate and compare the molecular and clinicopathologic features of CIMP-positive colorectal cancers defined by classic (p16, hMLH1, MINT1, MINT2, MINT31) and new (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1) CIMP panels. Design.—We analyzed 130 colorectal cancers for hypermethylation of both panels using methylation-specific polymerase chain reaction. Results.—With at least 2 markers methylated, both classic (39/130; 23.1%) and new (23.1%) CIMP-positive colorectal cancers were significantly associated with proximal tumor location, microsatellite instability, and BRAF mutation (all P values were less than .05). The new panel outperformed the classic panel in detecting these features. With at least 3 markers methylated, new CIMP-positive colorectal cancers (16.9%) were closely associated with proximal tumor location, low frequency of KRAS mutation, and high frequency of BRAF mutation (all P values were less than .05), whereas classic CIMP-positive colorectal cancers (18.5%) were closely associated with proximal tumor location, frequent microsatellite instability, and frequent BRAF mutation (all P values were less than .05). Analyzing a combination of CIMP and microsatellite instability status, CIMP-positive/microsatellite instability–negative colorectal cancers had the worst clinical outcomes. Conclusions.—Whereas the classic panel outperformed in predicting clinical outcome, the new panel was superior in detecting known clinicopathologic features of CIMP but inferior in prognostication power.

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A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis

Annals of Oncology ◽

10.1093/annonc/mdt076 ◽

2013 ◽

Vol 24 (8) ◽

pp. 2048-2056 ◽

Cited By ~ 55

Author(s):

C.C.J.M. Simons ◽

L.A.E. Hughes ◽

K.M. Smits ◽

C.A. Khalid-de Bakker ◽

A.P. de Bruïne ◽

...

Keyword(s):

Microsatellite Instability ◽

Chromosomal Instability ◽

Cpg Island ◽

Colorectal Tumors ◽

Cpg Island Methylator Phenotype ◽

Methylator Phenotype

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Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa042 ◽

2020 ◽

Vol 4 (5) ◽

Author(s):

Julia D Labadie ◽

Tabitha A Harrison ◽

Barbara Banbury ◽

Efrat L Amtay ◽

Sonja Bernd ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Cpg Island ◽

Distal Colon ◽

Tumor Location ◽

Proximal Colon ◽

Postmenopausal Hormone Therapy ◽

Cpg Island Methylator Phenotype ◽

Tumor Subtypes ◽

Methylator Phenotype

Abstract Background Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors. Conclusions We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

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