Title | Comprehensive molecular characterization of clear cell renal cell carcinoma. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Corporate Authors | Cancer Genome Atlas Research Network |
Journal | Nature |
Volume | 499 |
Issue | 7456 |
Pagination | 43-9 |
Date Published | 2013 Jul 04 |
ISSN | 1476-4687 |
Keywords | Acetyl-CoA Carboxylase, AMP-Activated Protein Kinases, Carcinoma, Renal Cell, Chromatin, Chromatin Assembly and Disassembly, Citric Acid Cycle, DNA Methylation, DNA Mutational Analysis, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Human, Genomics, GRB10 Adaptor Protein, Histone-Lysine N-Methyltransferase, Humans, Metabolic Networks and Pathways, MicroRNAs, Mutation, Pentose Phosphate Pathway, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, RNA, Neoplasm, Signal Transduction, Survival Analysis |
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. |
DOI | 10.1038/nature12222 |
Alternate Journal | Nature |
PubMed ID | 23792563 |
PubMed Central ID | PMC3771322 |
Grant List | U24 CA143882 / CA / NCI NIH HHS / United States U24 CA143866 / CA / NCI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States R01 HG005690 / HG / NHGRI NIH HHS / United States U24 CA143840 / CA / NCI NIH HHS / United States U24 CA143843 / CA / NCI NIH HHS / United States T32 CA071341 / CA / NCI NIH HHS / United States U24 CA143858 / CA / NCI NIH HHS / United States U24 CA143848 / CA / NCI NIH HHS / United States U54 HG003079 / HG / NHGRI NIH HHS / United States T32 CA082088 / CA / NCI NIH HHS / United States U24 CA143883 / CA / NCI NIH HHS / United States U24 CA143867 / CA / NCI NIH HHS / United States UL1 TR000005 / TR / NCATS NIH HHS / United States P30 CA016672 / CA / NCI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States R01 CA068490 / CA / NCI NIH HHS / United States K24 CA172355 / CA / NCI NIH HHS / United States U24 CA143835 / CA / NCI NIH HHS / United States U24 CA143845 / CA / NCI NIH HHS / United States U24 CA143799 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States U24 CA144025 / CA / NCI NIH HHS / United States |
Comprehensive molecular characterization of clear cell renal cell carcinoma.
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