Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Complete transcriptomic landscape of prostate cancer in the Chinese population using RNA-seq

ABSTRACT: There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs (long ncRNA), alternative splicing and somatic mutations. Three of the 14 tumors (21.4%) harbored a TMPRSS2-ERG fusion, and the low prevalence of this fusion in Chinese patients was further confirmed in an additional tumor set (10/54=18.5%). Notably, two novel gene fusions, CTAGE5-KHDRBS3 (20/54=37%) and USP9Y-TTTY15 (19/54=35.2%), occurred frequently in our patient cohort. Further systematic transcriptional profiling identified numerous long ncRNAs that were differentially expressed in the tumors. An analysis of the correlation between expression of long ncRNA and genes suggested that long ncRNAs may have functions beyond transcriptional regulation. This study yielded new insights into the pathogenesis of prostate cancer in the Chinese population.Cell Research advance online publication 21 February 2012; doi:10.1038/cr.2012.30.

ORGANISM(S): Homo sapiens

SUBMITTER: Jibin Zhang

PROVIDER: E-MTAB-567 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings.

Ren Shancheng S Peng Zhiyu Z Mao Jian-Hua JH Yu Yongwei Y Yin Changjun C Gao Xin X Cui Zilian Z Zhang Jibin J Yi Kang K Xu Weidong W Chen Chao C Wang Fubo F Guo Xinwu X Lu Ji J Yang Jun J Wei Min M Tian Zhijian Z Guan Yinghui Y Tang Liang L Xu Chuanliang C Wang Linhui L Gao Xu X Tian Wei W Wang Jian J Yang Huanming H Wang Jun J Sun Yinghao Y

Cell research 20120221 5

There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs (long ncRNA), alternative splicing and so ...[more]

PMID: 22349460

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Project description:Transcriptional profiling of LNCaP prostate cancer cells comparing control siRNA-treated LNCaP cells with LNCaP cells treated with siRNAs targeting Prostate Cancer Associated Transcript-1 (PCAT1), an uncharacterized long non-coding RNA. High-throughput sequencing of polyA+ RNA (RNA-Seq) in human cancer shows remarkable potential to identify both novel disease-specific markers for clinical uses and uncharacterized aspects of tumor biology, particularly non-coding RNA (ncRNA) species. To illustrate this approach, we employed RNA-Seq on a cohort of 102 prostate tissues and cells lines and found that aberrant expression profiles of novel tissue-specific ncRNAs distinguished benign, cancerous, and metastatic tumors. Among these, a novel prostate-cancer specific ncRNA (termed PCAT-1) defined a subset of aggressive cancers with low expression of the epigenetic regulator EZH2, a component of the Polycomb Repressive Complex 2 (PRC2) commonly upregulated in metastatic cancers. In vitro assays for core PRC2 genes indicated that the PRC2 complex directly binds and represses PCAT-1, and that the PCAT-1 transcript reciprocally binds PRC2, suggesting a regulatory feedback mechanism. Importantly, knockdown of PCAT-1 in cells with high levels of endogenous PCAT-1 transcript showed changes in cell proliferation and transcriptional regulation of several key biological processes, including cell cycle. Finally, we showed that ncRNA expression signatures, including PCAT-1, were effective for the non-invasive detection of prostate cancer, and that high ncRNA expression signature values correlate with high-grade histology. The findings presented herein establish the utility of RNA-Seq to comprehensively identify unannotated ncRNAs that define human disease states and characterize PCAT-1 as a novel regulator of cell proliferation mechanistically linked to PRC2 and contributory to translational clinical tests for prostate cancer. Two-condition experiment: Control-siRNA-treated versus PCAT1-siRNA-treated LNCaP cells. Biological replicates: 3 control replicates, 3 treatment replicates.

Project description:Many classes of noncoding RNAs (ncRNAs) are known to be involved in gene expression regulation; however, long intronic ncRNAs have received little attention. In previous works, our group has provided evidence that intronic regions, transcribed from 80% of all RefSeq gene loci, are key sources of potentially regulatory ncRNAs. Intronic transcripts were shown to be correlated to the degree of prostate cancer differentiation, regulated by physiological stimuli, and highly expressed in genomic loci related to transcriptional regulation. In the present work we aimed at functional characterization of KLHL29 intronic transcript, one of the most highly expressed in human tissues. Although the protein-coding KLHL29 transcripts are still poorly studied, genes from this family are involved in a wide variety of biological processes, including cell cycle regulation mechanisms. We have observed that the long intronic ncRNA is predominantly transcribed from the opposite strand at the KLHL29 locus, and that the ncRNA overexpression does not affect the levels of protein-coding mRNAs from the same locus. Intriguingly, we found 2,002 genes with significant (q< 5.3%) differential expression between HEK293 cells overexpressing KLHL29 sense (S) or antisense (AS) intronic transcript. Within these genes, GO categories such as ‘Regulation of cell cycle’ and ‘Transcription’ were significantly enriched. Furthermore, human tumorigenic cell lines overexpressing KLHL29 AS intronic transcript showed increased proliferation rates in vitro and increased tumorigenic capacity in nude mice. In conclusion, we suggest that KLHL29 long intronic ncRNA controls the cell cycle mechanisms, probably through a fine-tuning regulation of gene expression. Genes were defined as expressed when their intensity signals were above the average negative control value plus three standard deviations; a set of 153 negative controls (Agilent Technologies) was present on the array. Only genes that were detected as expressed in all four replicates of the same HEK293 transfection (or not expressed in the four replicates) were used in further analysis. The intensity values between experiments were normalized by the 40% trimmed mean intensity. For each transfection, one entire replicate experiment was excluded from the analyses, based on evaluating the coefficient of variance among the samples (for S KLHL29 intronic transcript, exclusion of the outlier replicate decreased the coefficient of variance from 0.21-0.24 (obtained by excluding any other replicate) to 0.19; for AS transcript, the coefficient of variance decreased from 0.17-0.18 to 0.12). Differentially expressed genes were identified using three transfection replicates for each construction, employing the Significance Analysis of Microarrays (SAM) tool (Tusher et al., 2001) with the following parameters: two-class response, 100 permutations and K-Nearest Neighbors Imputer. We applied 5.4 or 10.3% FDR (False Discovery Rate) cutoffs, as described in the results. A fold-change filter (1.4-fold cutoff) was applied after identification of significant differentially expressed genes.

Dataset Information

Complete transcriptomic landscape of prostate cancer in the Chinese population using RNA-seq

Publications

RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings.

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