Aberrant DOCK2, GRASP, HIF3A and PKFP Hypermethylation has Potential as a Prognostic Biomarker for Prostate Cancer

Abstract

Prostate cancer (PCa) is a clinically heterogeneous disease and currently, accurate diagnostic and prognostic molecular biomarkers are lacking. This study aimed to identify novel DNA hypermethylation markers for PCa with future potential for blood-based testing. Accordingly, to search for genes specifically hypermethylated in PCa tissue samples and not in blood cells or other cancer tissue types, we performed a systematic analysis of genome-wide DNA methylation data (Infinium 450K array) available in the Marmal-aid database for 4072 malignant/normal tissue samples of various types. We identified eight top candidate markers (cg12799885, DOCK2, FBXO30, GRASP, HIF3A, MOB3B, PFKP, and TPM4) that were specifically hypermethylated in PCa tissue samples and hypomethylated in other benign and malignant tissue types, including in peripheral blood cells. Potential as diagnostic and prognostic biomarkers was further assessed by the quantitative methylation specific PCR (qMSP) analysis of 37 nonmalignant and 197 PCa tissue samples from an independent population. Here, all eight hypermethylated candidates showed high sensitivity (75–94%) and specificity (84–100%) for PCa. Furthermore, DOCK2, GRASP, HIF3A and PKFP hypermethylation was significantly associated with biochemical recurrence (BCR) after radical prostatectomy (RP; 197 patients), independent of the routine clinicopathological variables. DOCK2 is the most promising single candidate marker (hazard ratio (HR) (95% confidence interval (CI)): 1.96 (1.24–3.10), adjusted p = 0.016; multivariate cox regression). Further validation studies are warranted and should investigate the potential value of these hypermethylation candidate markers for blood-based testing also.

Genomic landscape of the immune microenvironments of brain metastases in breast cancer

“…Hu et al [57] have reported that low expression of DOCK2 is associated with poorer prognosis of acute myeloid leukemia. Recent study reported that DOCK2 hypermethylation was associated with biochemical recurrence after radical prostatectomy in prostate cancer [58]. To our knowledge, there was no study about the role of DOCK2 in breast cancer.…”

Epigenetic Analysis of Circulating Tumor DNA in Localized and Metastatic Prostate Cancer: Evaluation of Clinical Biomarker Potential

“…Here, three of these markers (COL4A6, GABRE, KLF8) were excluded as they showed hypermethylation in PBCs (Figure 1 and Figure S1). Additionally, a set of 11 PCa-specifically hypermethylated biomarker candidates (previously identified from the Marmal-aid database [14]) were also included ( Figure 1 and Figure S1). Thus, for the present study, a total of 24 biomarker candidates significantly hypermethylated in PCa tissue (n = 187) compared to PBC samples (n = 876), normal prostate tissue samples (n = 81), tissue samples from 14 other cancer types (n = 2042), and other normal tissue samples (n = 598) were selected for further evaluation of their PCa-biomarker potential in plasma (p < 0.001, Mann-Whitney test, Figure S1).…”

Advances in Prognostic Methylation Biomarkers for Prostate Cancer

“…We refer readers to the original studies for the full lists of methylation markers. We focus on those studies that used measures of disease risk to identify potential biomarkers (for example, comparing methylation of patients of different GS, or different survival outcomes), rather than studies that compared methylation differences between benign and tumour tissue to identify disease-specific biomarkers, with assessment of their prognostic value as only a secondary step [ 113 , 114 , 115 , 116 , 117 , 118 , 119 ].…”