Distinct DNA methylation alterations are associated with cribriform architecture and intraductal carcinoma in Gleason pattern 4 prostate tumors

Abstract

Abstract. The aim of the present study was to explore DNA methylation aberrations in association with cribriform architecture and intraductal carcinoma (IDC) of the prostate, as there is robust evidence that these morphological features are associated with aggressive disease and have significant clinical implications. Herein, the associations of a panel of seven known prognostic DNA methylation biomarkers with cribriform and IDC features were examined in a series of 91 Gleason pattern (GP) 4 tumors derived from Gleason score 7 radical prostatectomies. Gene specific DNA methylation was compared between cribriform and/or IDC positive vs. negative cases, and in association with clinicopathological features, using Chi square and Mann-Whitney U tests. DNA methylation of the adenomatous polyposis coli, Ras association domain family member 1 and T-box 15 genes was significantly elevated in GP4 tumors with cribriform and/or IDC features compared with negative cases (P=0.045, P=0.007 and P=0.013, respectively). To the best of our knowledge, this provides the first evidence for an association between cribriform and/or IDC and methylation biomarkers, and warrants further investigation of additional DNA methylation events in association with various architectural patterns in prostate cancer. IntroductionProstate cancer (PCa) is the second most common type of cancer affecting men worldwide, with an incidence of 1.1 million new cases each year (1). The most widely accepted pathological grading of PCa is the Gleason Score (GS), which is based on architectural features of the gland and is comprised of the sum of two Gleason Patterns (GP) (2). The GS grading system is among the most effective predictors of clinical outcomes following radical prostatectomy (RP), and is universally used to guide PCa treatment (3). Within this system, GS6 PCas are low grade, whereas GS8 or higher are classified as high grade. GS7 prostate adenocarcinomas consisting of variable proportions of GP3 and GP4 are considered to be intermediate grade, and represent the most heterogeneous group of neoplasms with diverse clinical outcomes (4,5) Thus, GS7 PCa is the focus of the current study, as identifying specific prognostic factors that can provide additional information on disease progression and treatment outcomes for patients with GS7 PCa would be of marked clinical benefit. GP4 is assigned to adenocarcinomas when they contain any of the following architectural patterns: Small/large fused glands, poorly formed glands, glomeruloid and cribriform architecture (4-6). The cribriform pattern is commonly associated with intraductal carcinoma (IDC), a distinct histopathological entity characterized by malignant cells spanning the lumen of prostate ducts and acini (7-9). Although specific morphologies of PCa, including cribriform architecture and IDC, have been recognized for decades, their independent clinical significance is only now emerging (8). Studies have demonstrated that IDC in biopsy and/or RP tissues is indicative Distinct DNA methylation alteration...

Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

“…This implies the presence of occult metastases at the time of treatment, which are not accurately predicted using standard clinical prognostic factors. We and others have used multi-omic approaches to identify candidate biomarkers that predict BCR 7 – 10 , 51 – 53 . While BCR is an early and easily measured endpoint, it is a weak surrogate of prostate cancer-specific mortality 5 , 6 .…”

Intraductal Carcinoma of the Prostate as a Cause of Prostate Cancer Metastasis: A Molecular Portrait

“…Additionally, Olkhov-Mitsel et al [109] investigated the methylation profile of ALU, APC, CYP26A1, HOXD3, HOXD8, RASSF1, TBX15, TGF-β in IDC-P/CC lesions from 91 Gleason score 7 PCas and found an increase in the methylation levels of APC, RASSF15 and TBX15 in IDC-P/CC.…”

Molecular complexity of intraductal carcinoma of the prostate

“…Biologically, MED12 serves as an important regulator of the Wnt pathway, encompassing both canonical Wnt signaling and Wnt/PCP signaling 89 . A study demonstrated increased methylation levels of the APC gene in IDC‐P lesions, which further contributes to the activation of the Wnt pathway 21 . Furthermore, In a study focusing on BRCA2 ‐mutant prostate cancers, it was observed that tumors with IDC‐P exhibited a higher prevalence of genomic and epigenomic dysregulation of MED12 11 .…”