低、高Gleason评分前列腺癌患者原发性肿瘤及相应淋巴结转移灶中的DNA甲基化和基因组拷贝数
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.
作者信息
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
机构信息
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer", Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
出版信息
Clin Transl Radiat Oncol. 2023 Jan 21;39:100586. doi: 10.1016/j.ctro.2023.100586. eCollection 2023 Mar.
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.
目的
在前列腺癌中，对临床淋巴结阴性患者进行盆腔淋巴通路照射的指征仅基于临床列线图。为了确定淋巴转移的生物学风险模式，我们研究了原发性肿瘤及相应淋巴结转移灶中的DNA甲基化和基因组拷贝数。
方法/患者：分析了前列腺切除术后和淋巴结切除术后，来自 Gleason 评分（GS）-6/7a（n = 20 例淋巴结阳性，n = 20 例淋巴结阴性）和 GS-9/10 患者（淋巴结阳性 n = 20）的原发性肿瘤（PT）和配对的同步淋巴结转移灶（LN）的 DNA 甲基化和基因组拷贝数谱。
结果
GS-6/7a pN0 PTs 和 GS-6/7a pN1 PTs 在组蛋白 H3K27me3/H3K9me3 介导的甲基化方面存在差异。与 LN 相比，在 GS-6/7a pN1 和 GS-9/10 pN1 患者的 PT 中，除了染色体区域 11q13.1、14q11.2 和 15q26.1 的拷贝数变化外，组蛋白 H3K4me1/2 介导的 DNA 甲基化也存在很大差异。在 GS-6/7a pN1 和 GS-9/10 pN1 患者之间，比较 LN 时甲基化水平的差异比比较 PT 时更大。16q21 - 22.1 在 GS-9/10 pN0 PTs 中特异性缺失。免疫系统相关通路表征了 GS-6/7a pN1 和 GS-9/10 pN1 患者的 PT 与 LN 之间的差异。比较 GS-6/7a pN1 和 GS-9/10 pN1 患者的 PT 和 LK 发现跨膜和 G 蛋白偶联受体信号传导发生改变。
结论
我们的数据表明，前列腺癌的进展，包括淋巴转移，与组蛋白介导的 DNA 甲基化有关，并且我们假设存在一种甲基化特征可预测 GS-6/7a 患者原发性肿瘤中的淋巴转移。GS-6/7a 患者的淋巴转移，伴有 DNA 甲基化和拷贝数改变，似乎比 GS-9/10 患者更复杂，在 GS-9/10 患者中，原发性肿瘤似乎已经具有促使淋巴结转移的改变。
Zotero 插件