透明细胞肾细胞癌的光学基因组和表观基因组定位。

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2025-03-07 eCollection Date: 2025-03-01 DOI:10.1093/narcan/zcaf008
Sapir Margalit, Zuzana Tulpová, Yael Michaeli, Tahir Detinis Zur, Jasline Deek, Sivan Louzoun-Zada, Gil Nifker, Assaf Grunwald, Yuval Scher, Leonie Schütz, Elmar Weinhold, Yehudit Gnatek, Dorit Omer, Benjamin Dekel, Eitan Friedman, Yuval Ebenstein
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引用次数: 0

摘要

癌细胞表现出复杂的基因组畸变,包括大规模的基因重排和表观遗传调节,这些不容易被短读测序捕获。本研究提出了一种新的方法来同时分析匹配癌症样本的远程遗传和表观遗传变化,重点是透明细胞肾细胞癌(ccRCC)。ccRCC是一种常见的肾癌亚型,通常以3p缺失和von Hippel-Lindau (VHL)基因失活为特征。我们对配对肿瘤和邻近非肿瘤组织样本进行了综合遗传学、细胞遗传学和表观遗传学分析。光学基因组图谱鉴定出基因组畸变为结构和拷贝数变异,补充了外显子组测序结果。单分子甲基组和羟甲基组图谱显示,两种样品对的5hmC水平均显著降低,并观察到表观遗传信号与基因表达之间的相关性。单分子表观遗传学分析发现了许多差异修饰区域,其中一些与ccRCC的发病机制有关,包括VHL、PRCC和PBRM1基因。值得注意的是,与代谢和癌症发展相关的途径在这些差异区域中显著丰富。本研究证明了整合光学基因组和表观基因组图谱对匹配肿瘤和邻近组织进行综合表征的可行性,揭示了已建立的和新的体细胞畸变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Optical genome and epigenome mapping of clear cell renal cell carcinoma.

Cancer cells display complex genomic aberrations that include large-scale genetic rearrangements and epigenetic modulation that are not easily captured by short-read sequencing. This study presents a novel approach for simultaneous profiling of long-range genetic and epigenetic changes in matched cancer samples, focusing on clear cell renal cell carcinoma (ccRCC). ccRCC is a common kidney cancer subtype frequently characterized by a 3p deletion and the inactivation of the von Hippel-Lindau (VHL) gene. We performed integrated genetic, cytogenetic, and epigenetic analyses on paired tumor and adjacent nontumorous tissue samples. Optical genome mapping identified genomic aberrations as structural and copy number variations, complementing exome-sequencing findings. Single-molecule methylome and hydroxymethylome mapping revealed a significant global reduction in 5hmC level in both sample pairs, and a correlation between both epigenetic signals and gene expression was observed. The single-molecule epigenetic analysis identified numerous differentially modified regions, some implicated in ccRCC pathogenesis, including the genes VHL, PRCC, and PBRM1. Notably, pathways related to metabolism and cancer development were significantly enriched among these differential regions. This study demonstrates the feasibility of integrating optical genome and epigenome mapping for comprehensive characterization of matched tumor and adjacent tissue, uncovering both established and novel somatic aberrations.

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CiteScore
6.90
自引率
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审稿时长
13 weeks
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