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

PURPOSE: 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 correspond...

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Detalles Bibliográficos
Autores principales: Unger, Kristian, Hess, Julia, Link, Vera, Buchner, Alexander, Eze, Chukwuka, Li, Minglun, Stief, Christian, Kirchner, Thomas, Klauschen, Frederick, Zitzelsberger, Horst, Niyazi, Maximilian, Ganswindt, Ute, Schmidt-Hegemann, Nina-Sophie, Belka, Claus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Special Issue on Personalized Radiation Oncology; Edited by Daniel Zips, Pierre Blanchard
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014335/
https://www.ncbi.nlm.nih.gov/pubmed/36935856
http://dx.doi.org/10.1016/j.ctro.2023.100586
Descripción
Sumario:PURPOSE: 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. METHODS/PATIENTS: 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. RESULTS: 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. CONCLUSIONS: 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.

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