Promoter Methylation of PRKCB, ADAMTS12, and NAALAD2 Is Specific to Prostate Cancer and Predicts Biochemical Disease Recurrence

Abstract

The molecular diversity of prostate cancer (PCa) has been demonstrated by recent genome-wide studies, proposing a significant number of different molecular markers. However, only a few of them have been transferred into clinical practice so far. The present study aimed to identify and validate novel DNA methylation biomarkers for PCa diagnosis and prognosis. Microarray-based methylome data of well-characterized cancerous and noncancerous prostate tissue (NPT) pairs was used for the initial screening. Ten protein-coding genes were selected for validation in a set of 151 PCa, 51 NPT, as well as 17 benign prostatic hyperplasia samples. The Prostate Cancer Dataset (PRAD) of The Cancer Genome Atlas (TCGA) was utilized for independent validation of our findings. Methylation frequencies of ADAMTS12, CCDC181, FILIP1L, NAALAD2, PRKCB, and ZMIZ1 were up to 91% in our study. PCa specific methylation of ADAMTS12, CCDC181, NAALAD2, and PRKCB was demonstrated by qualitative and quantitative means (all p < 0.05). In agreement with PRAD, promoter methylation of these four genes was associated with the transcript down-regulation in the Lithuanian cohort (all p < 0.05). Methylation of ADAMTS12, NAALAD2, and PRKCB was independently predictive for biochemical disease recurrence, while NAALAD2 and PRKCB increased the prognostic power of multivariate models (all p < 0.01). The present study identified methylation of ADAMTS12, NAALAD2, and PRKCB as novel diagnostic and prognostic PCa biomarkers that might guide treatment decisions in clinical practice.

A Distinct Glucose Metabolism Signature of Lung Adenocarcinoma With Prognostic Value

“…DHDH had been reported to be included in a metabolism-related prognostic signature for hepatocellular carcinoma ( Yang et al, 2021 ). PRKCB has also been reported to be included in the prognostic signature for adult T-cell leukemia/lymphoma and prostate cancer ( Kataoka et al, 2018 ; Daniunaite et al, 2021 ). INPP5J regulates AKT1-dependent breast cancer growth and metastasis and predicts recurrence in lung adenocarcinoma ( Ooms et al, 2015 ; Zhang et al, 2020 ).…”

PRKCB is a novel and potential biomarker in colon cancer and shapes an inflamed tumor immune microenvironment

“…PRKCB mutation occurs commonly in adult T-cell leukemia/lymphoma, and is an independent poor prognostic factor [26]. Methylation of PRKCB is also one of the biomarkers of prognosis and predicting recurrence of prostate cancer [27]. However, there is not much research on the role of PRKCB in TIME of colon cancer.…”

Analysis of Intrinsic Breast Cancer Subtypes: The Clinical Utility of Epigenetic Biomarkers and TP53 Mutation Status in Triple-Negative Cases

“…For DNA methylation assessment, the pairs of primers specific to methylated (M) and unmethylated (U) sequences within the 5‘region of P14 , P16 , MGMT, RARB, RASSF1, DAPK1, GSTP1, ESR1 (two 5′ regions of the ESR1 gene, one in promoter region and one intragenic sequence, were included into this study and marked as ESR1-1 and ESR1-4 , respectively), PRKCB, MT1E, MT1F, MT1G, APC, ADAMTS12 , and RUNX3. Genes were designed using Methyl Primer Express v1.0 software (Applied Biosystems (ABI), TFS) or selected based on BC specificity and diagnostic and/or outcome prediction capabilities from our previous studies [ 27 , 28 , 29 ] (see Supplementary Table S3 ). Methylation-specific PCR (MSP) mix of the final volume of 25 µL contained 10 ng of bisulfite-modified DNA template, PCR buffer, 1.6 mM of each dNTP, 2.5 mM of MgCl2, 1 µM of each primer, enhancer, and 0.5 U of Gold polymerase (ABI, TFS).…”