Article

Comprehensive molecular characterization of clear cell renal cell carcinoma.

1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. [2] Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature (Impact Factor: 42.35). 06/2013; DOI: 10.1038/nature12222
Source: PubMed

ABSTRACT Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.

Full-text

Available from: Christopher Ricketts, Jul 03, 2014

Click to see the full-text of:

Article: Comprehensive molecular characterization of clear cell renal cell carcinoma.

2.38 MB

See full-text
2 Followers
 · 
187 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chimeric read-through RNAs are transcripts originating from two directly adjacent genes (<10 kb) on the same DNA strand. Although they are found in next-generation whole transcriptome sequencing (RNA-Seq) data on a regular basis, investigating them further has usually been refrained from. Therefore, their expression patterns or functions in general, and in oncogenesis in particular, are poorly understood. We used paired-end RNA-Seq and a specifically designed computational data analysis pipeline (FusionSeq) to nominate read-through events in a small discovery set of renal cell carcinomas (RCC) and confirmed them in a larger validation cohort. 324 read-through events were called overall; 22/27 (81%) selected nominees passed validation with conventional PCR and were sequenced at the junction region. We frequently identified various isoforms of a given read-through event. 2/22 read-throughs were up-regulated: BC039389-GATM was higher expressed in RCC compared to benign adjacent kidney; KLK4-KRSP1 was expressed in 46/169 (27%) RCCs, but rarely in normal tissue. KLK4-KRSP1 expression was associated with worse clinical outcome in the patient cohort. In cell lines, both read-throughs influenced molecular mechanisms (i.e. target gene expression or migration/invasion) in a way that counteracted the effect of the respective parent transcript GATM or KLK4. Our data suggests that the up-regulation of read-through RNA chimeras in tumors is not random but causes regulatory effects on cellular mechanisms and may impact patient survival.
    BMC Genomics 03/2015; 16(1):247. DOI:10.1186/s12864-015-1446-z · 4.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Much progress has been made in the treatment of metastatic renal cell carcinoma (RCC) over the last decade, with the development of agents that block the vascular endothelial growth factor (VEGF) pathway or the mammalian target of rapamycin (mTOR) pathway. The incorporation of these agents into treatment algorithms has been the result of carefully conducted clinical trials leading to Food and Drug Administration (FDA) approval and subsequent adoption as the current standard of care. These trials, however, were dominated by patients with clear cell renal cell carcinoma (ccRCC), and little data are currently available on the treatment of non-clear cell renal cell carcinoma (nccRCC). nccRCC encompasses a biologically heterogeneous group of kidney tumors that portend very diverse prognoses and responses to therapy. This review is a pathway based approach that highlights the current systemic treatment strategies for metastatic nccRCC.
    Frontiers in Oncology 04/2015; 5. DOI:10.3389/fonc.2015.00067
  • [Show abstract] [Hide abstract]
    ABSTRACT: Deregulated Notch signaling is linked to a variety of tumors and it is therefore important to learn more about the frequency and distribution of Notch mutations in a tumor context. In this report, we use data from the recently developed Cancer Cell Line Encyclopedia to assess the frequency and distribution of Notch mutations in a large panel of cancer cell lines in silico. Our results show that the mutation frequency of Notch receptor and ligand genes is at par with that for established oncogenes and higher than for a set of house-keeping genes. Mutations were found across all four Notch receptor genes, but with notable differences between protein domains, mutations were for example more prevalent in the regions encoding the LNR and PEST domains in the Notch intracellular domain. Furthermore, an in silico estimation of functional impact showed that deleterious mutations cluster to the ligand-binding and the intracellular domains of NOTCH1. For most cell line groups, the mutation frequency of Notch genes is higher than in associated primary tumors. Our results shed new light on the spectrum of Notch mutations after in vitro culturing of tumor cells. The higher mutation frequency in tumor cell lines indicates that Notch mutations are associated with a growth advantage in vitro, and thus may be considered to be driver mutations in a tumor cell line context.
    BMC Cancer 04/2015; 15(1):311. DOI:10.1186/s12885-015-1278-x · 3.32 Impact Factor