Abstract：
At present, the extent and clinical relevance of epigenetic differences between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) remain largely unknown. Here, we conducted a study to describe the global DNA methylation landscape of UTUC and UCB and to address the prognostic value of DNA methylation subtype and responses to the DNA methyltransferase inhibitor SGI-110 in urothelial carcinoma (UC).
Using whole-genome bisulfite sequencing (n = 49 samples), we analyzed epigenomic features and profiles of UTUC (n = 36) and UCB (n = 9). Next, we characterized potential links between DNA methylation, gene expression (n = 9 samples), and clinical outcomes. Then, we integrated an independent UTUC cohort (Fujii et al., n = 86) and UCB cohort (TCGA, n = 411) to validate the prognostic significance. Furthermore, we performed an integrative analysis of genome-wide DNA methylation and gene expression in two UC cell lines following transient DNA methyltransferase inhibitor SGI-110 treatment to identify potential epigenetic driver events that contribute to drug efficacy.
We showed that UTUC and UCB have very similar DNA methylation profiles. Unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes. Methy-High samples were hypermethylated, immune-infiltrated, and enriched for exhausted T cells, with poor clinical outcome. SGI-110 inhibited the migration and invasion of Methy-High UC cell lines (UMUC-3 and T24) by upregulating multiple antitumor immune pathways.
DNA methylation subtypes pave the way for predicting patient prognosis in UC. Our results provide mechanistic rationale for evaluating SGI-110 in treating UC patients in the clinic.
Using whole-genome bisulfite sequencing (n = 49 samples), we analyzed epigenomic features and profiles of UTUC (n = 36) and UCB (n = 9). Next, we characterized potential links between DNA methylation, gene expression (n = 9 samples), and clinical outcomes. Then, we integrated an independent UTUC cohort (Fujii et al., n = 86) and UCB cohort (TCGA, n = 411) to validate the prognostic significance. Furthermore, we performed an integrative analysis of genome-wide DNA methylation and gene expression in two UC cell lines following transient DNA methyltransferase inhibitor SGI-110 treatment to identify potential epigenetic driver events that contribute to drug efficacy.
We showed that UTUC and UCB have very similar DNA methylation profiles. Unsupervised DNA methylation classification identified two epi-clusters, Methy-High and Methy-Low, associated with distinct muscle-invasive statuses and patient outcomes. Methy-High samples were hypermethylated, immune-infiltrated, and enriched for exhausted T cells, with poor clinical outcome. SGI-110 inhibited the migration and invasion of Methy-High UC cell lines (UMUC-3 and T24) by upregulating multiple antitumor immune pathways.
DNA methylation subtypes pave the way for predicting patient prognosis in UC. Our results provide mechanistic rationale for evaluating SGI-110 in treating UC patients in the clinic.
摘要：
目前,上尿路尿路上皮癌(UTUC)和膀胱尿路上皮癌(UCB)之间的表观遗传差异的程度和临床相关性仍在很大程度上未知.这里,我们进行了一项研究,以描述UTUC和UCB的全球DNA甲基化情况,并探讨DNA甲基化亚型和DNA甲基转移酶抑制剂SGI-110在尿路上皮癌(UC)中的预后价值.
使用全基因组亚硫酸氢盐测序（n=49个样本），我们分析了UTUC(n=36)和UCB(n=9)的表观基因组特征和谱.接下来,我们表征了DNA甲基化之间的潜在联系，基因表达（n=9个样本），和临床结果。然后，我们整合了一个独立的UTUC队列(Fujii等人。,n=86)和UCB队列(TCGA，n=411)以验证预后意义。此外，我们对瞬时DNA甲基转移酶抑制剂SGI-110治疗后两种UC细胞系的全基因组DNA甲基化和基因表达进行了综合分析,以鉴定有助于药物疗效的潜在表观遗传驱动事件.
我们表明UTUC和UCB具有非常相似的DNA甲基化谱。无监督DNA甲基化分类确定了两个外延簇，Methy-High和Methy-Low,与不同的肌肉侵入状态和患者预后相关。高甲基样品被高度甲基化，免疫浸润,富集耗尽的T细胞，临床结果不佳。SGI-110通过上调多种抗肿瘤免疫途径抑制Methy-HighUC细胞系(UMUC-3和T24)的迁移和侵袭。
DNA甲基化亚型为预测UC患者的预后铺平了道路。我们的结果为临床上评估SGI-110治疗UC患者提供了机制依据。
使用全基因组亚硫酸氢盐测序（n=49个样本），我们分析了UTUC(n=36)和UCB(n=9)的表观基因组特征和谱.接下来,我们表征了DNA甲基化之间的潜在联系，基因表达（n=9个样本），和临床结果。然后，我们整合了一个独立的UTUC队列(Fujii等人。,n=86)和UCB队列(TCGA，n=411)以验证预后意义。此外，我们对瞬时DNA甲基转移酶抑制剂SGI-110治疗后两种UC细胞系的全基因组DNA甲基化和基因表达进行了综合分析,以鉴定有助于药物疗效的潜在表观遗传驱动事件.
我们表明UTUC和UCB具有非常相似的DNA甲基化谱。无监督DNA甲基化分类确定了两个外延簇，Methy-High和Methy-Low,与不同的肌肉侵入状态和患者预后相关。高甲基样品被高度甲基化，免疫浸润,富集耗尽的T细胞，临床结果不佳。SGI-110通过上调多种抗肿瘤免疫途径抑制Methy-HighUC细胞系(UMUC-3和T24)的迁移和侵袭。
DNA甲基化亚型为预测UC患者的预后铺平了道路。我们的结果为临床上评估SGI-110治疗UC患者提供了机制依据。
