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Mol Cancer Res. 2019 Jan;17(1):84-96. doi: 10.1158/1541-7786.MCR-17-0636. Epub 2018 Aug 21.

Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis.

Author information

1
Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama.
2
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
3
Department of Medical Oncology, Dana Farber Cancer Institute, Massachusetts.
4
Department of Medicine, Section of Hematology-Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
5
Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia Pennsylvania.
6
Department of Molecular Medicine, University of Texas Health Sciences Center at San Antonio, Texas.
7
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama. sudarshan@uab.edu soorya@uab.edu.
8
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
9
Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
10
Department of Urology, University of Alabama at Birmingham, Birmingham, Alabama. sudarshan@uab.edu soorya@uab.edu.
11
Birmingham Veterans Affairs Medical Center, Birmingham, Alabama.
#
Contributed equally

Abstract

The Cancer Genome Atlas (TCGA) and other large-scale genomic data pipelines have been integral to the current understanding of the molecular events underlying renal cell carcinoma (RCC). These data networks have focused mostly on primary RCC, which often demonstrates indolent behavior. However, metastatic disease is the major cause of mortality associated with RCC and data sets examining metastatic tumors are sparse. Therefore, a more comprehensive analysis of gene expression and DNA methylome profiling of metastatic RCC in addition to primary RCC and normal kidney was performed. Integrative analysis of the methylome and transcriptome identified over 30 RCC-specific genes whose mRNA expression inversely correlated with promoter methylation, including several known targets of hypoxia inducible factors. Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation including hexokinase 2, aldolase C, stearoyl-CoA desaturase, and estrogen-related receptor-γ (ESRRG), which has a known role in the regulation of nuclear-encoded mitochondrial metabolism genes. Several gene expression changes could portend prognosis in the TCGA cohort. Mechanistically, ESRRG loss occurs via DNA methylation and histone repressive silencing mediated by the polycomb repressor complex 2. Restoration of ESRRG in RCC lines suppresses migratory and invasive phenotypes independently of its canonical role in mitochondrial metabolism. IMPLICATIONS: Collectively, these data provide significant insight into the biology of aggressive RCC and demonstrate a novel role for DNA methylation in the promotion of HIF signaling and invasive phenotypes in renal cancer.

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