Dataset Information

Establishment of Novel DNA Methylation-Based Prostate Cancer Subtypes and a Risk-Predicting Eight-Gene Signature.

ABSTRACT: Prostate cancer (PCa) is the most common malignant tumor affecting males worldwide. The substantial heterogeneity in PCa presents a major challenge with respect to molecular analyses, patient stratification, and treatment. Least absolute shrinkage and selection operator was used to select eight risk-CpG sites. Using an unsupervised clustering analysis, called consensus clustering, we found that patients with PCa could be divided into two subtypes (Methylation_H and Methylation_L) based on the DNA methylation status at these CpG sites. Differences in the epigenome, genome, transcriptome, disease status, immune cell composition, and function between the identified subtypes were explored using The Cancer Genome Atlas database. This analysis clearly revealed the risk characteristics of the Methylation_H subtype. Using a weighted correlation network analysis to select risk-related genes and least absolute shrinkage and selection operator, we constructed a prediction signature for prognosis based on the subtype classification. We further validated its effectiveness using four public datasets. The two novel PCa subtypes and risk predictive signature developed in this study may be effective indicators of prognosis.

SUBMITTER: Zhang E

PROVIDER: S-EPMC7940376 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Establishment of Novel DNA Methylation-Based Prostate Cancer Subtypes and a Risk-Predicting Eight-Gene Signature.

Zhang Enchong E Shiori Fujisawa F Mu Oscar YongNan OY He Jieqian J Ge Yuntian Y Wu Hongliang H Zhang Mo M Song Yongsheng Y

Frontiers in cell and developmental biology 20210223

Prostate cancer (PCa) is the most common malignant tumor affecting males worldwide. The substantial heterogeneity in PCa presents a major challenge with respect to molecular analyses, patient stratification, and treatment. Least absolute shrinkage and selection operator was used to select eight risk-CpG sites. Using an unsupervised clustering analysis, called consensus clustering, we found that patients with PCa could be divided into two subtypes (Methylation_H and Methylation_L) based on the DN ...[more]

PMID: 33708770

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Project description:BackgroundThere is significant heterogeneity in prostate cancer (PCa), but immune status can reflect its prognosis. This study aimed to explore immune-related gene-based novel subtypes and to use them to create a model predicting the risk of PCa.MethodsWe downloaded the data of 487 PCa patients from The Cancer Genome Atlas (TCGA) database. We used immunologically relevant genes as input for consensus clustering and applied survival analysis and principal component analysis to determine the properties of the subtypes. We also explored differences of somatic variations, copy number variations, TMPRSS2-ERG fusion, and androgen receptor (AR) scores among the subtypes. Then, we examined the infiltration of different immune cells into the tumor microenvironment in each subtype. We next performed Gene Set Enrichment Analysis (GSEA) to illustrate the characteristics of the subtypes. Finally, based on the subtypes, we constructed a risk predictive model and verified it in TCGA, Gene Expression Omnibus (GEO), cBioPortal, and International Cancer Genome Consortium (ICGC) databases.ResultsFour PCa subtypes (C1, C2, C3, and C4) were identified on immune status. Patients with the C3 subtype had the worst prognosis, while the other three groups did not differ significantly from each other in terms of their prognosis. Principal component analysis clearly distinguished high-risk (C3) and low-risk (C1 + 2 + 4) patients. Compared with the case in the low-risk subtype, the Speckle-type POZ Protein (SPOP) had a higher mutation frequency and lower transcriptional level in the high-risk subtype. In C3, there was also a higher frequency of copy number alterations (CNA) of Clusterin (CLU) and lower CLU expression. In addition, C3 had a higher frequency of TMPRSS2-ERG fusion and higher AR scores. M2 macrophages also showed significantly higher infiltration in the high-risk subtype, while CD8+ T cells and dendritic cells had significantly higher infiltration in the low-risk subtype. GSEA revealed that MYC, androgen, and KRAS were relatively activated and p53 was relatively suppressed in high-risk subtype, compared with the levels in the low-risk subtype. Finally, we trained a six-gene signature risk predictive model, which performed well in TCGA, GEO, cBioPortal, and ICGC databases.ConclusionPCa can be divided into four subtypes based on immune-related genes, among which the C3 subtype is associated with a poor prognosis. Based on these subtypes, a risk predictive model was developed, which could indicate patient prognosis.

Project description:BackgroundThis study aimed to explore the prognostic role of DNA methylation pattern in endometrial cancer (EC) patients.MethodsDifferentially methylated genes (DMGs) of EC patients with distinct survival from The Cancer Genome Atlas (TCGA) database were analyzed to identify methylated genes as biomarkers for EC prognosis. The Least Absolute Shrinkage and Selection Operator (LASSO) analysis was used to construct a risk score model. A nomogram was built based on analysis combining the risk score model with clinicopathological signatures together, and then verified in the validation cohort and patients in our own center.ResultsIn total, 157 DMGs were identified between different prognostic groups. Based on the LASSO analysis, five genes (GBP4, OR8K3, GABRA2, RIPPLY2, and TRBV5-7) were screened for the establishment of risk score model. The model outperformed in prognostic accuracy at varying follow-up times (AUC for 3 years: 0.824, 5 years: 0.926, and 7 years: 0.853). Multivariate analysis identified four independent risk factors including menopausal status (HR = 3.006, 95%CI: 1.062-8.511, p = 0.038), recurrence (HR = 2.116, 95%CI: 1.061-4.379, p = 0.046), lymph node metastasis (LNM, HR = 3.465, 95%CI: 1.225-9.807, p = 0.019), and five-DNA methylation risk model (HR = 3.654, 95%CI: 1.458-9.161, p = 0.006) in training cohort. The performance of the nomogram was good in the training (AUC = 0.828), validation (AUC = 0.866) and the whole cohorts (AUC = 0.843). Furthermore, we verified the nomogram with 24 patients in our center and the Kaplan-Meier survival curve also proved to be significantly different (p < 0.01). The subgroup analysis in different stratifications indicated that the accuracy was high in different subgroups for age, histological type, tumor grade, and clinical stage (all p < 0.01).ConclusionsBriefly, our work established and verified a five-DNA methylation risk model, and a nomogram merging the model with clinicopathological characteristics to facilitate individual prediction of EC patients for clinicians.

Project description:BackgroundPatients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity.Materials and methodsGenome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity.ResultsIntegrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT.ConclusionsA promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.

Dataset Information

Establishment of Novel DNA Methylation-Based Prostate Cancer Subtypes and a Risk-Predicting Eight-Gene Signature.

Publications

Establishment of Novel DNA Methylation-Based Prostate Cancer Subtypes and a Risk-Predicting Eight-Gene Signature.

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