Differentially methylated CpG sites associated with the high-risk group of prostate cancer

Anastasiya Kobelyatskaya,Kirill Nyushko,Andrey Kaprin,Anna Kudryavtseva,Maria Fedorova,Dmitry Trofimov,Elena Pudova,Boris Alekseev,Gennady Sukhikh,Sergey Razin,George Krasnov,Anastasia Snezhkina

doi:10.1515/jib-2020-0031

Abstract

Prostate cancer (PC) is one of the most common and socially significant oncological diseases among men. Bioinformatic analysis of omics data allows identifying molecular genetic changes associated with the disease development, as well as markers of prognosis and response to therapy. Alterations in DNA methylation and histone modification profiles widely occur in malignant tumors. In this study, we analyzed changes in DNA methylation in three groups of PC patients based on data from The Cancer Genome Atlas project (TCGA, https://portal.gdc.cancer.gov): (1) high- and intermediate-risk of the tumor progression, (2) favorable and unfavorable prognoses within the high-risk group, and (3) TMPRSS2-ERG-positive (tumors with TMPRSS2-ERG fusion transcript) and TMPRSS2-ERG-free cases within the high-risk group. We found eight CpG sites (cg07548607, cg13533340, cg16643088, cg18467168, cg23324953, cg23753247, cg25773620, and cg27148952) hypermethylated in the high-risk group compared with the intermediate-risk group of PC. Seven differentially methylated CpG sites (cg00063748, cg06834698, cg18607127, cg25273707, cg01704198, cg02067712, and cg02157224) were associated with unfavorable prognosis within the high-risk group. Six CpG sites (cg01138171, cg14060519, cg19570244, cg24492886, cg25605277, and cg26228280) were hypomethylated in TMPRSS2-ERG-positive PC compared to TMPRSS2-ERG-negative tumors within the high-risk group. The CpG sites were localized, predominantly, in regulatory genome regions belonging to promoters of the following genes: ARHGEF4, C6orf141, C8orf86, CLASP2, CSRNP1, GDA, GSX1, IQSEC1, MYOF, OR10A3, PLCD1, PLEC1, PRDM16, PTAFR, RP11-844P9.2, SCYL3, VPS13D, WT1, and ZSWIM2. For these genes, analysis of differential expression and its correlation with CpG site methylation (β-value level) was also performed. In addition, STK33 and PLCD1 had similar changes in colorectal cancer. As for the CSRNP1, the ARHGEF4, and the WT1 genes, misregulated expression levels were mentioned in lung, liver, pancreatic and androgen-independent prostate cancer. The potential impact of changed methylation on the mRNA level was determined for the CSRNP1, STK33, PLCD1, ARHGEF4, WT1, SCYL3, and VPS13D genes. The above CpG sites could be considered as potential prognostic markers of the high-risk group of PC.

Highlights

Prostate cancer (PC, MeSH - D011471) is a common malignant neoplasm in men worldwide [1]
3.1 Differentially methylated CpG sites associated with the high-risk group of PC
These CpG sites were located in the promoters of the following genes [27,28,29,30]: ZSWIM2, GDA, CSRNP1, IQSEC1, PLEC1, STK33, PLCD1, and C6orf141, respectively (Table 2)

Summary

Introduction

Prostate cancer (PC, MeSH - D011471) is a common malignant neoplasm in men worldwide [1]. To predict the course of PC, patients are stratified into appropriate risk groups based on the following criteria: pathological stage of the tumor (pT), prostate-specific antigen (PSA) level before surgery, and Gleason score [2]. These criteria often incorrectly reflect the aggressive tumor phenotype. Epigenetic changes occur in all types of malignant tumors and include perturbation of both the DNA methylation and the histone modification patterns [3, 4] These changes can be associated with various clinical and pathological characteristics and, in some cases, allow to conclude about the prognosis [3]. For PC, global DNA hypomethylation is almost always associated with the late stages of the disease and is usually found in metastatic tissues [5]

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Discussion

Conclusion