Abstract
Abstract Molecular markers for metastatic prostate cancer (PCa) can be identified by sequencing metastatic tumor genomes. We recently identified cancer gene mutations in a patient with metastatic disease using next generation sequencing (NGS) of DNA from 5 metastatic tumors and blood. We characterized a somatic non-conservative substitution in the methylcytosine dioxygenase ten-eleven translocation 2 (TET2) in all metastatic tumors but not the blood or primary adenocarcinoma. Analysis of metastatic tumors from additional patients revealed frequent somatic loss and sequence alteration of TET2, which was previously observed to be altered in 5-15% of myeloid, kidney and colon cancer. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma, and rare germline missense variants are observed in African-Americans with PCa. We sought to further investigate the role of TET2 in PCa. We performed fine-mapping of PCa risk across the TET2 locus using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Electrophoretic mobility shift assays show two risk SNPs are bound by the transcription factor octamer-binding protein 1 (Oct1). Full length TET2 (2002 aa) is expressed in normal prostate and cancer tissue and is significantly reduced in a subset of the Cancer Genome Atlas (TCGA) PCa tumors that are associated with metastatic disease and reduced disease-free survival. TET2-loss drives a cancer phenotype as siRNA-mediated knockdown (KD) significantly increases LNCaP and DU145 cell proliferation, and LNCaP transwell migration and wound healing. Affinity chromatography, mass spectrometry and co-immunoprecipitation confirm that endogenous TET2 binds the androgen receptor (AR) in LNCaP cell extracts. TET2 KD alters the expression of a subset of androgen-responsive genes including increased prostate-specific antigen (KLK3/PSA) expression, and published data indicate TET-catalyzed hydroxymethylcytosine (hmC) and TET2 binding sites proximal to KLK3. Analysis of TCGA PCa tumor RNA-seq reveals TET2 expression is co-regulated with the expression of genes encoding functions metabolizing 2-oxoglutarate and succinate including the lysine demethylase KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1-2, SDHA-B and FH. Co-expression is conserved across all 31 TCGA cancers examined. Examination of genomic locations associated with TET2-binding and hmC, and gene expression changes during androgen signaling indicate a putative role for TET2 as an energy sensor that modifies androgen-AR signaling. Decreased TET2 mRNA expression in TCGA PCa tumors that are associated with reduced patient survival indicates TET2 expression may be an informative biomarker of PCa disease progression. Citation Format: Michael L. Nickerson, Sudipto Das, Kate Im, Sevilay Turan, Sonja Berndt, Hongchuan Li, Hong Lou, Seth Brodie, Kalpit Shah, Jean-Noel Billaud, Tongwu Zhang, Joseph Boland, Stephen Anderson, Meredith Yeager, Michael Dean, Thorkell Andresson. TET2-loss modifies androgen signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2017-355
Published Version
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