title: Identification of DNA Methylation-Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma.
abstract: 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. Cancer Res; 76(7); 1954-64. ©2016 AACR.
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Elinne
authors.initials: E
authors.lastname: Becket
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Sameer
authors.initials: S
authors.lastname: Chopra
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Duymich
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, School of Medicine Konkuk University, Seoul, Korea.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Kurinji
authors.initials: K
authors.lastname: Pandiyan
authors.affiliation: Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nichols
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Jessica
authors.initials: J
authors.lastname: Charlet
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. gliang@usc.edu.
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics / Q000379:methods*; D015870:Gene Expression; D006801:Humans