DNA-methylation and genomic copy number in primary tumors and corresponding lymph node metastases in prostate cancer from patients with low and high Gleason score

Abstract

In prostate cancer, the indication to irradiate the pelvic lymphatic pathways in clinical node-negative patients is solely based on clinical nomograms. To define biological risk patterns of lymphatic spread, we studied DNA-methylation and genomic copy number in primary tumors and corresponding lymph nodes metastases. DNA-methylation and genomic copy number profiles of primary tumors (PT) and paired synchronous lymph node metastases (LN) from Gleason Score (GS)-6/7a (n=20 LN-positive, n=20 LN-negative) and GS-9/10 patients (LN-positive n=20) after prostatectomy and lymphonodectomy were analyzed. GS-6/7a pN0 PTs and GS-6/7a pN1 PTs differed in histone H3K27me3/H3K9me3 mediated methylation. PTs compared to LNs, in both, GS-6/7a pN1 and GS-9/10 pN1 patients showed large differences in DNA-methylation mediated by histones H3K4me1/2, in addition to copy number changes of chromosomal regions 11q13.1, 14q11.2 and 15q26.1. Between GS-6/7a pN1 and GS-9/10 pN1 patients, methylation levels differed more when comparing LNs than PTs. 16q21-22.1 was specifically lost in GS-9/10 pN0 PTs. Immune system-related pathways characterized the differences between PTs and LNs in both GS-6/7a pN1 and GS-9/10 pN1 patients. Comparing PTs and LKs between GS-6/7a pN1 and GS-9/10 pN1 patients revealed altered transmembrane and G-protein-coupled receptor signaling. Our data suggest that progression of prostate cancer, including lymphatic spread, is associated with histone-mediated DNA-methylation and we hypothesize a methylation signature predicting lymphatic spread in GS-6/7a patients from primary tumors. Lymphatic spread in GS-6/7a patients, flanked by DNA-methylation and CNA alterations, appears to be more complex than in GS-9/10 patients, in whom the primary tumors already appear to bear lymph node metastasis-enabling alterations.