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Title: Next-generation sequencing of translocation renal cell carcinoma reveals novel RNA splicing partners and frequent mutations of chromatin-remodeling Genes
Authors: Malouf, G.G
Su, X
Yao, H
Gao, J
Xiong, L
He, Q
Compérat, E
Couturier, J
Molinié, V
Escudier, B
Camparo, P
Doss, D.J
Thompson, E.J
Khayat, D
Wood, C.G
Yu, W 
Teh, B.T 
Weinstein, J
Tannir, N.M
Keywords: inhibitor of differentiation 2
microphthalmia associated transcription factor
phosphatidylinositol 3 kinase
transcription factor
transcription factor E
transforming growth factor beta1
unclassified drug
DNA helicase
INO80 protein, human
KHDRBS2 protein, human
KHSRP protein, human
messenger RNA
RED120 protein, human
RNA binding protein
transactivator protein
tumor marker
cancer incidence
cell cycle S phase
cell line
cell proliferation
chromatin assembly and disassembly
chromatin remodeling gene
controlled study
gene expression
gene silencing
gene technology
gene translocation
genetic association
human cell
INO80D gene
KHDRBS2 gene
KHSRP gene
kidney cancer
kidney carcinoma
LUC7L3 gene
mutation rate
next generation sequencing
priority journal
RNA sequence
RNA splicing
translocation renal cell carcinoma
cell cycle
enzyme immunoassay
gene expression regulation
genome-wide association study
high throughput sequencing
kidney tumor
mutation rate
real time polymerase chain reaction
reverse transcription polymerase chain reaction
RNA splicing
tumor cell culture
Western blotting
Biomarkers, Tumor
Blotting, Western
Carcinoma, Renal Cell
Cell Cycle
Cell Proliferation
Chromatin Assembly and Disassembly
DNA Helicases
Gene Expression Regulation, Neoplastic
Genome-Wide Association Study
High-Throughput Nucleotide Sequencing
Immunoenzyme Techniques
Kidney Neoplasms
Mutation Rate
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
RNA Splicing
RNA, Messenger
RNA-Binding Proteins
Translocation, Genetic
Tumor Cells, Cultured
Issue Date: 2014
Publisher: American Association for Cancer Research Inc.
Citation: Malouf, G.G, Su, X, Yao, H, Gao, J, Xiong, L, He, Q, Compérat, E, Couturier, J, Molinié, V, Escudier, B, Camparo, P, Doss, D.J, Thompson, E.J, Khayat, D, Wood, C.G, Yu, W, Teh, B.T, Weinstein, J, Tannir, N.M (2014). Next-generation sequencing of translocation renal cell carcinoma reveals novel RNA splicing partners and frequent mutations of chromatin-remodeling Genes. Clinical Cancer Research 20 (15) : 4129-4140. ScholarBank@NUS Repository.
Abstract: Purpose: MITF/TFE 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. Experimental Design: We performed RNA and exome sequencingon anexploratory set of TRCC(n =7), and validated ourfindingsusing The Cancer Genome Atlas (TCGA) clear-cellRCC(ccRCC) dataset(n=460). Results: Using the TCGA dataset, we identified seven TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP, and KHDRBS2) that are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared with other RCC types, and showed activationof MITF, the transforming growth factor?1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed adistinct mutational spectrumascompared 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 INO80D, an ATP-dependent chromatin-remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3-TFE3 translocation. Conclusions: This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin-remodeling genes. © 2014 American Association for Cancer Research.
Source Title: Clinical Cancer Research
ISSN: 1078-0432
DOI: 10.1158/1078-0432.CCR-13-3036
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