scholarly journals CpG Island Methylator Phenotype Modulates the Immune Response of the Tumor Microenvironment and Influences the Prognosis of Pancreatic Cancer Patients

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Gang Ning ◽  
Yongqiang Li ◽  
Wenji Chen ◽  
Wenjuan Tang ◽  
Diwen Shou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Clustering Analysis ◽  
Cpg Island ◽  
Consensus Clustering ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Methylator Phenotype

Background. CpG island methylator phenotype (CIMP), featured with concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have investigated the role of CIMP in pancreatic cancer (PC). The aim of this study was to explore the CIMP in PC patients and its impact on the immune response of the tumor microenvironment and prognosis. Methods. DNA methylation, somatic mutation, mRNA, and corresponding clinical data of PC patients were downloaded from TCGA (184 patients) and the ICGC (264 patients). Univariate and multivariate regression analyses were used to identify prognosis-related CpGs. Consensus clustering analysis was used for identification of the CIMP in PC patients. ESTIMATE and CIBORORT were used for estimation of the tumor microenvironment (TME) in PC patients. Results. In the TCGA PC cohort, 22,450 differential CpGs, including 12,937 hypermethylated CpGs and 9,513 hypomethylated CpGs, were identified between 184 PC patients and 10 normal controls. Univariate and multivariate Cox analysis further screened out 72 OS-related CpGs, and three distinct CIMP groups with distinctly different prognosis and molecular features, including the CIMP-L subgroup, CIMP-M subgroup, and CIMP-H subgroup, were identified based on unsupervised consensus clustering analysis of these CpGs. Patients of the CIMP-H subgroup had poorer OS and RFS, while patients of the CIMP-L subgroup had better OS and RFS. The CIMP status was also an independent prognostic factor for OS and PFS. In molecular features, significantly higher somatic mutation burden and tumor mutational burden were found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. Besides, lower stromal score, immune score, and higher cancer stemness indices and tumor purity were also found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. Correspondingly, significant total T cells, total B cells, CD8 T cells, memory CD4 T cells, and higher regulatory T cells were found in patients of the CIMP-H subgroup. Moreover, significantly lower expression of immune checkpoint genes, such as PD-1, CTLA4, CD86, VTCN1, and LAG-3, was also found in patients of the CIMP-H subgroup compared to those of the CIMP-L subgroup. In the end, we validated the CIMP status in PC patients of the ICGC dataset. Conclusion. The CIMP may modulate the immune response of the tumor microenvironment and influence the prognosis of pancreatic cancer patients, which may help to make an assertion to provide specific and efficient treatment options for patients of different subtypes.

scholarly journals Cpg Island Methylator Phenotype With Distinctly Different Prognosis And Molecular Features In Pancreatic Cancer Patient

2021 ◽  
Author(s):  
Gang Ning ◽  
Yongqiang Li ◽  
Wenji Chen ◽  
Wenjuan Tang ◽  
Diwen Shou ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Somatic Mutation ◽  
Clustering Analysis ◽  
Cpg Island ◽  
Consensus Clustering ◽  
Cpg Island Methylator Phenotype ◽  
Efficient Treatment ◽  
Molecular Features ◽  
Methylator Phenotype

Abstract BackgroundCpG island methylator phenotype (CIMP), featured with concurrent and widespread hypermethylation of a cluster of CpGs, has been reported to play an important role in carcinogenesis. Limited studies have investigated the CIMP in pancreatic cancer (PC). The aim of this study was to explore the CIMP in PC patients and its clinical-pathological and genomic characteristics. Methods:DNA methylation, somatic mutation, mRNA and corresponding clinical data of PC patients were downloaded from TCGA (184 patients) and ICGC (264 patients). Univariate and multivariate regression analysis were used to identify prognosis related CpGs. Consensus clustering analysis was used for identification of the CIMP in PC patients. ESTIMATE and CIBORORT were used for estimation of tumor microenvironment (TME) in PC patients.ResultsIn TCGA PC cohort, 22,450 differential CpGs, including 12,937 hypermethylated CpGs and 9,513 hypomethylated CpGs were identified between185 PC patients and 10 normal controls. Univariate and multivariate Cox analysis further screened out 72 OS related CpGs and three distinct CIMP groups with distinctly different prognosis and molecular features, including CIMP-L subgroup, CIMP-M subgroup and CIMP-H subgroup were identified based on unsupervised consensus clustering analysis of these CpGs. Patients of the CIMP-H subgroup had poorer OS and RFS, while patients of CIMP-L subgroup had better OS and RFS. The CIMP status were also an independent prognostic factors for OS and PFS. In molecular features, significantly higher somatic mutation burdens and tumor mutational burden were found at patients of CIMP-H subgroup compared to that in patients of CIMP-L subgroup. Besides, lower stromal score, immune score and higher cancer stemness indices and tumor purity were also found at patients of CIMP-H subgroup compared to that in patients of CIMP-L subgroup. Correspondingly, significantly total T cells, total B cells, CD8 T cells, memory CD4 T cells and higher regulatory T cells were found at patients of CIMP-H subgroup. Moreover, significantly lower expression of immune checkpoint genes, such as PD-1, CTLA4, CD86, VTCN1 and LAG-3 were also found at patients of CIMP-H subgroup compared to that in patients of CIMP-L subgroup. In the end, we validated the CIMP status in PC patients of ICGC dataset.ConclusionThree distinct CIMP subgroups of PC patients with distinct clinical characteristic, prognosis, gene mutation landscape and TME were identified and validated. The CIMP may help to make an assertion to provide specific and efficient treatment options for patients of different subtypes.

scholarly journals How theBRAFV600E Mutation Defines a Distinct Subgroup of Colorectal Cancer: Molecular and Clinical Implications

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Catherine E. Bond ◽  
Vicki L. J. Whitehall
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Early Event ◽  
Sporadic Colorectal Cancer ◽  
Cpg Island Methylator Phenotype ◽  
Distinct Subgroup ◽  
Molecular Features ◽  
Map Kinase Pathway ◽  
Methylator Phenotype ◽  
Kinase Pathway

TheBRAFoncogene is an integral component of the MAP kinase pathway, and an activating V600E mutation occurs in 15% of sporadic colorectal cancer. This is an early event in serrated pathway tumourigenesis, and theBRAFV600E has been commonly associated with the CpG island methylator phenotype, microsatellite instability (MSI), and a consistent clinical presentation including a proximal location and predilection for elderly females. A proportion of theBRAFmutant lesions remain as microsatellite stable (MSS), and in contrast to the MSI cancers, they have an aggressive phenotype and correlate with poor patient outcomes. Recent studies have found that they have clinical and molecular features of both theBRAFmutant/MSI and the conventionalBRAFwild-type cancers and comprise a distinct colorectal cancer subgroup. This review highlights the importance of theBRAFmutation occurring in colorectal cancer stratified for molecular background and discusses its prognostic and clinical significance.

scholarly journals Molecular Subtypes of Colorectal Cancer and Their Clinicopathologic Features, With an Emphasis on the Serrated Neoplasia Pathway

2016 ◽  
Vol 140 (5) ◽  
pp. 406-412 ◽  
Author(s):  
Jeong Mo Bae ◽  
Jung Ho Kim ◽  
Gyeong Hoon Kang
Keyword(s):  
Colorectal Cancer ◽  
Complex Disease ◽  
Molecular Subtypes ◽  
Cpg Island ◽  
Colorectal Cancers ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Methylator Phenotype ◽  
Serrated Neoplasia Pathway ◽  
Molecular Carcinogenesis

Context.—Colorectal cancer is a heterogeneous disease entity with 3 molecular carcinogenesis pathways and 2 morphologic multistep pathways. Right-sided colon cancers and left-sided colon and rectal cancers exhibit differences in their incidence rates according to geographic region, age, and sex. A linear tendency toward increasing frequencies of microsatellite instability–high or CpG island methylator phenotype–high cancers in subsites along the bowel from the rectum to the cecum or the ascending colon accounts for the differences in tumor phenotypes associated with these subsites. The molecular subtypes of colorectal cancers exhibit different responses to adjuvant therapy, which might be responsible for differences in subtype-specific survival. Objectives.—To review the clinicopathologic and molecular features of the molecular subtypes of colorectal cancer generated by combined CpG island methylator phenotype and microsatellite statuses, to integrate these features with the most recent findings in the context of the prognostic implications of molecular subtypes, and to emphasize the necessity of developing molecular markers that enable the identification of adenocarcinomas involving the serrated neoplasia pathway. Data Sources.—Based on the authors' own experimental data and a review of the pertinent literature. Conclusions.—Because colorectal cancers arise from 2 different morphologic multistep carcinogenesis pathways with varying contributions from 3 different molecular carcinogenesis pathways, colorectal cancer is a heterogeneous and complex disease. Thus, molecular subtyping of colorectal cancers is an important approach to characterizing their heterogeneity with respect to not only prognosis and therapeutic response but also biology and natural history.

scholarly journals Unique characteristics of CpG island methylator phenotype (CIMP) in a Chinese population with colorectal cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiang Liu ◽  
Li Tang ◽  
Jinhua Yi ◽  
Guimei Li ◽  
Youwang Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Chinese Population ◽  
Cpg Island ◽  
Molecular Characteristics ◽  
Cpg Island Methylator Phenotype ◽  
Chinese Populations ◽  
Molecular Features ◽  
Tumour Location ◽  
Low Incidence ◽  
Methylator Phenotype

Abstract Background Molecular characteristics of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been well documented in Western, but not in Chinese, populations. Methods We investigated the incidence of CIMP, BRAF/KRAS mutation, and microsatellite instability (MSI) in a Chinese population with CRC (n = 401) and analysed associations between CIMP status and clinicopathological and molecular features. Results A total of 41 cases, 310 cases, and 40 cases were classified as CIMP-high, CIMP-low, and CIMP-negative, respectively. We detected a significantly low incidence of BRAF mutation in adenomas (2%) and CRC (0.7%), and a relatively low incidence of KRAS mutation (24.9%) compared with that in other populations. We also detected a relatively low incidence of CIMP-high (10.2%), which was significantly associated with younger age (≤49 years of age), female sex, and proximal tumour location. Conclusions This study revealed unique characteristics of CIMP in a Chinese population with colorectal cancer. Developing specific CIMP markers based on unique populations or ethnic groups will further help to fully elucidate CIMP pathogenesis.

scholarly journals Association of the Colorectal CpG Island Methylator Phenotype with Molecular Features, Risk Factors, and Family History

2015 ◽  
Vol 24 (3) ◽  
pp. 512-519 ◽  
Author(s):  
Daniel J. Weisenberger ◽  
A. Joan Levine ◽  
Tiffany I. Long ◽  
Daniel D. Buchanan ◽  
Rhiannon Walters ◽  
...  
Keyword(s):  
Risk Factors ◽  
Family History ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Methylator Phenotype

Four Molecular Subtypes of Colorectal Cancer and Their Precursor Lesions

2011 ◽  
Vol 135 (6) ◽  
pp. 698-703
Author(s):  
Gyeong Hoon Kang
Keyword(s):  
Molecular Subtypes ◽  
Cpg Island ◽  
Colorectal Carcinogenesis ◽  
Colorectal Cancers ◽  
Precursor Lesions ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Epigenetic Instability ◽  
Geographic Differences ◽  
Methylator Phenotype

Abstract Context.—In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI−, CIMP−/MSI+, and CIMP−/MSI−. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. Objective.—To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. Data Sources.—This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). Conclusion.—The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.

scholarly journals Tracking the Features of CIMP-positive Glioma: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Huashi Xiao ◽  
Yingying Xu ◽  
He-chun Shen ◽  
Wanjun Liu ◽  
Siyuan Tan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cpg Island ◽  
Meta Analysis ◽  
Clinicopathological Features ◽  
Cochrane Library ◽  
Cpg Island Methylator Phenotype ◽  
Independent Prognostic Marker ◽  
Molecular Features ◽  
Hazard Ratios ◽  
Methylator Phenotype

Abstract Backgrounds Controversy surrounding CpG island methylator phenotype (CIMP) in glioma exists with regard to its prognostic value.Methods PubMed, EMBASE, and Cochrane Library databases were searched for studies describing molecular and clinicopathological features, and overall survival of gliomas stratified by CIMP status. Associations of CIMP with outcome parameters were estimated using odds ratio (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) using a fixed or random effects model.Results A total of 12 studies involving 2386 gliomas (1051 CIMP-positive and 1335 CIMP-negative) were included. Molecular analysis showed that CIMP is more frequent in IDH1-mutated gliomas (OR 229.07; 95% CI 138.72–378.26) and 1p19q LOH gliomas (OR 5.65; 95% CI 2.66–12.01), though CIMP was not associated with EGFR mutation (OR 0.14; 95% CI 0.05–0.43) or MGMT promoter methylation (OR 3.01; 95% CI 0.79–11.48). Clinicopathological analysis showed that CIMP is more frequent in oligodendroglioma (OR 5.51; 95% CI 3.95–7.70), but less frequent in glioblastoma (OR 0.14; 95% CI 0.10–0.19). However, CIMP was not associated with anaplastic oligoastrocytomas (OR 1.57; 95% CI 1.24-2.00) or oligoastrocytoma (OR 0.79; 95% CI 0.35–1.76). We found that CIMP-positive glioma was associated with a longer overall survival (HR -0.57; 95% CI -0.97– -0.16).Conclusions A CIMP-positive glioma has better prognosis and its own molecular features (such as IDH1 and 1p19q LOH mutations) and clinicopathological features. These conditions suggest CIMP could be used as an independent prognostic marker for glioma.

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