Dataset Information

A Qualitative Transcriptional Signature for Predicting CpG Island Methylator Phenotype Status of the Right-Sided Colon Cancer.

ABSTRACT: A part of colorectal cancer which is characterized by simultaneous numerous hypermethylation CpG islands sites is defined as CpG island methylator phenotype (CIMP) status. Stage II and III CIMP-positive (CIMP+) right-sided colon cancer (RCC) patients have a better prognosis than CIMP-negative (CIMP-) RCC treated with surgery alone. However, there is no gold standard available in defining CIMP status. In this work, we selected the gene pairs whose relative expression orderings (REOs) were associated with the CIMP status, to develop a qualitative transcriptional signature to individually predict CIMP status for stage II and III RCC. Based on the REOs of gene pairs, a signature composed of 19 gene pairs was developed to predict the CIMP status of RCC through a feature selection process. A sample is predicted as CIMP+ when the gene expression orderings of at least 12 gene pairs vote for CIMP+; otherwise the CIMP-. The difference of prognosis between the predicted CIMP+ and CIMP- groups was more significantly different than the original CIMP status groups. There were more differential methylation and expression characteristics between the two predicted groups. The hierarchical clustering analysis showed that the signature could perform better for predicting CIMP status of RCC than current methods. In conclusion, the qualitative transcriptional signature for classifying CIMP status at the individualized level can predict outcome and guide therapy for RCC patients.

SUBMITTER: You T

PROVIDER: S-EPMC7658404 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Qualitative Transcriptional Signature for Predicting CpG Island Methylator Phenotype Status of the Right-Sided Colon Cancer.

You Tianyi T Song Kai K Guo Wenbing W Fu Yelin Y Wang Kai K Zheng Hailong H Yang Jing J Jin Liangliang L Qi Lishuang L Guo Zheng Z Zhao Wenyuan W

Frontiers in genetics 20201029

A part of colorectal cancer which is characterized by simultaneous numerous hypermethylation CpG islands sites is defined as CpG island methylator phenotype (CIMP) status. Stage II and III CIMP-positive (CIMP+) right-sided colon cancer (RCC) patients have a better prognosis than CIMP-negative (CIMP-) RCC treated with surgery alone. However, there is no gold standard available in defining CIMP status. In this work, we selected the gene pairs whose relative expression orderings (REOs) were associa ...[more]

PMID: 33193579

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Project description:Background & aimsThe CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL).MethodsWe analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated.ResultsOf the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses.ConclusionsPatients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Project description:BackgroundGastric cancer (GC) is one of the most fatal cancers in the world. Results of previous studies on the association of the CpG island methylator phenotype (CIMP) with GC prognosis are conflicting and mainly based on selected CIMP markers. The current study attempted to comprehensively assess the association between CIMP status and GC survival and to develop a CIMP-related prognostic gene signature of GC.MethodsWe used a hierarchical clustering method based on 2,082 GC-related methylation sites to stratify GC patients from the cancer genome atlas into three different CIMP subgroups according to the CIMP status. Gene set enrichment analysis, tumor-infiltrating immune cells, and DNA somatic mutations analysis were conducted to reveal the genomic characteristics in different CIMP-related patients. Cox regression analysis and the least absolute shrinkage and selection operator were performed to develop a CIMP-related prognostic signature. Analyses involving a time-dependent receiver operating characteristic (ROC) curve and calibration plot were adopted to assess the performance of the prognostic signature.ResultsWe found a positive relationship between CIMP and prognosis in GC. Gene set enrichment analysis indicated that cancer-progression-related pathways were enriched in the CIMP-L group. High abundances of CD8+ T cells and M1 macrophages were found in the CIMP-H group, meanwhile more plasma cells, regulatory T cells and CD4+ memory resting T cells were detected in the CIMP-L group. The CIMP-H group showed higher tumor mutation burden, more microsatellite instability-H, less lymph node metastasis, and more somatic mutations favoring survival. We then established a CIMP-related prognostic gene signature comprising six genes (CST6, SLC7A2, RAB3B, IGFBP1, VSTM2L and EVX2). The signature was capable of classifying patients into high-and low-risk groups with significant difference in overall survival (OS; p < 0.0001). To assess performance of the prognostic signature, the area under the ROC curve (AUC) for OS was calculated as 0.664 at 1 year, 0.704 at 3 years and 0.667 at 5 years. When compared with previously published gene-based signatures, our CIMP-related signature was comparable or better at predicting prognosis. A multivariate Cox regression analysis indicated the CIMP-related prognostic gene signature was an independent prognostic indicator of GC. In addition, Gene ontology analysis indicated that keratinocyte differentiation and epidermis development were enriched in the high-risk group.ConclusionCollectively, we described a positive association between CIMP status and prognosis in GC and proposed a CIMP-related gene signature as a promising prognostic biomarker for GC.

Dataset Information

A Qualitative Transcriptional Signature for Predicting CpG Island Methylator Phenotype Status of the Right-Sided Colon Cancer.

Publications

A Qualitative Transcriptional Signature for Predicting CpG Island Methylator Phenotype Status of the Right-Sided Colon Cancer.

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