Data from Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes

Abstract

<div>Abstract<p><b>Purpose:</b><i>MITF/TFE</i> translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated.</p><p><b>Experimental Design:</b> We performed RNA and exome sequencing on an exploratory set of TRCC (<i>n</i> = 7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (<i>n</i> = 460).</p><p><b>Results:</b> Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of <i>MITF/TFE</i> (<i>LUC7L3</i>, <i>KHSRP</i>, and <i>KHDRBS2</i>) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activation of <i>MITF</i>, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for <i>MITF</i> and <i>ID2</i> targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared with ccRCC, with frequent mutations in chromatin-remodeling genes (six of eight cases, three of which were from the TCGA). In two cases, we identified mutations in <i>INO80D</i>, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of <i>INO80D</i> decreased cell proliferation in a novel cell line bearing <i>LUC7L3–TFE3</i> translocation.</p><p><b>Conclusions:</b> This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel <i>MITF/TFE</i> partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes. <i>Clin Cancer Res; 20(15); 4129–40. ©2014 AACR</i>.</p></div>