Identification of DNA Methylation-Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma

被引:29
作者
Becket, Elinne [1 ]
Chopra, Sameer [1 ]
Duymich, Christopher E. [1 ]
Lin, Justin J. [2 ]
You, Jueng Soo [3 ]
Pandiyan, Kurinji [1 ]
Nichols, Peter W. [4 ]
Siegmund, Kimberly D. [5 ]
Charlet, Jessica [1 ]
Weisenberger, Daniel J. [6 ]
Jones, Peter A. [1 ,7 ]
Liang, Gangning [1 ]
机构
[1] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Urol, Los Angeles, CA 90033 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Konkuk Univ, Sch Med, Dept Biochem, Seoul, South Korea
[4] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Pathol, Los Angeles, CA 90033 USA
[5] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA
[6] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA
[7] Van Andel Res Inst, Grand Rapids, MI USA
关键词
CANCER GENOME; GENE; EXPRESSION; SIGNATURES;
D O I
10.1158/0008-5472.CAN-15-2622
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Alterations in chromatin accessibility independent of DNA methylation can affect cancer-related gene expression, but are often overlooked in conventional epigenomic profiling approaches. In this study, we describe a cost-effective and computationally simple assay called AcceSssIble to simultaneously interrogate DNA methylation and chromatin accessibility alterations in primary human clear cell renal cell carcinomas (ccRCC). Our study revealed significant perturbations to the ccRCC epigenome and identified gene expression changes that were specifically attributed to the chromatin accessibility status whether or not DNA methylation was involved. Compared with commonly mutated genes in ccRCC, such as the von Hippel-Lindau (VHL) tumor suppressor, the genes identified by AcceSssIble comprised distinct pathways and more frequently underwent epigenetic changes, suggesting that genetic and epigenetic alterations could be independent events in ccRCC. Specifically, we found unique DNA methylation-independent promoter accessibility alterations in pathways mimicking VHL deficiency. Overall, this study provides a novel approach for identifying new epigenetic-based therapeutic targets, previously undetectable by DNA methylation studies alone, that may complement current genetic-based treatment strategies.
引用
收藏
页码:1954 / 1964
页数:11
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