DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations.
DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations.
复制标题
前列腺癌脑转移的DNA甲基化景观是由早期驱动器遗传改变塑造的。
DOI：
10.1158/0008-5472.can-22-2236
复制
发表时间：
2023-04-14
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
DNA甲基化分析揭示了PCBM的分子特征，可以作为鉴定和靶向这些罕见转移的易感性的起点。从原发性前列腺癌转移到罕见部位，如大脑，正变得越来越普遍，因为改进的治疗方法延长了预期寿命。表观遗传失调是原发性前列腺癌的一个特征，不同的DNA甲基化谱已被证明与相互排斥的spop突变或TMPRSS2-ERG融合遗传背景相关。研究人员对42例前列腺癌脑转移（PCBM）患者进行了DNA甲基化分析，以研究原发性前列腺癌和PCBM之间的表观遗传差异、表观遗传改变与突变背景之间的关系，以及可能与PCBM相关的特定表观遗传改变。PCBM的多区域取样揭示了转移灶内的表观遗传稳定性。PCBM中的异常甲基化与突变背景和PRC2复合物活性相关，这种影响在spop突变的PCBM中尤为明显。虽然PCBM表现出CpG岛高甲基化表型，但也观察到参与神经活性配体受体相互作用和细胞粘附分子（如GABRB3、CLDN8和CLDN4）的基因启动子的低甲基化，这表明原发肿瘤细胞可能需要特异性重编程才能形成脑转移。本研究揭示了PCBM的DNA甲基化景观以及PCBM相关的异常DNA甲基化的潜在机制和影响。DNA甲基化分析揭示了PCBM的分子特征，可以作为鉴定和靶向这些罕见转移的易感性的起点。
DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases. Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
影响因子：
6.6
作者：
Gallon J;Coto-Llerena M;Ercan C;Bianco G;Paradiso V;Nuciforo S;Taha-Melitz S;Meier MA;Boldanova T;Pérez-Del-Pulgar S;Rodríguez-Tajes S;von Flüe M;Soysal SD;Kollmar O;Llovet JM;Villanueva A;Terracciano LM;Heim MH;Ng CKY;Piscuoglio S
通讯作者：
Piscuoglio S