Clear cell renal cell carcinoma pathways (WP4018)
Inactivation of VHL due to mutation or DNA methylation is an early event in ccRCC that leads to accumulation of the transcription factor HIF-α, which dimerizes with HIF-β and translocates to the nucleus. The resulting HIF-α–HIF-β-induced up-regulation of downstream genes promotes cell proliferation, glucose uptake, glycolysis, and angiogenesis. Mutations in chromatin remodelers and histone modifiers including PBRM1, SETD2, BAP1 and KDM5C lead to global abnormal gene expression patterns, and deficiency in DNA repair, which contributes to genomic instability. Activation of PI3K–mTOR signaling promotes cell proliferation and tumor aggression, and increases translation of HIF-α, leading to enhanced HIF-α-mediated gene expression. The proposed development pattern of ccRCC is based on tumor evolution analyses and current understanding of genomic variation. Description adapted from "Precision medicine from the renal cancer genome", Riazalhosseini and Lathrop. Additional sources of information: mTORC1 complex is based on [https://en.wikipedia.org/wiki/Mechanistic_target_of_rapamycin#mTORC1 Wikipedia]. PDGFB and TGFB as targets of HIF1A based on [http://www.genome.jp/kegg-bin/show_pathway?hsa05211 KEGG].
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Authors

Alex Pico , Kristina Hanspers , Egon Willighagen , and Eric Weitz

Cited In

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Organism

Homo sapiens

Communities

CPTAC Diseases Renal Genomics Pathways

Annotations

Disease Ontology: clear cell renal cell carcinoma

Cell Type Ontology: kidney cell kidney proximal convoluted tubule epithelial cell

Pathway Ontology: signaling pathway

Participants

Label Type Compact Identifier
glucose Metabolite chebi:17234
DEPTOR GeneProduct ensembl:ENSG00000155792
ACACA GeneProduct ensembl:ENSG00000278540
KCNJ2 GeneProduct ensembl:ENSG00000123700
EFCAB3 GeneProduct ensembl:ENSG00000172421
FASN GeneProduct ensembl:ENSG00000169710
ENPP3 GeneProduct ensembl:ENSG00000154269
HK3 GeneProduct ensembl:ENSG00000160883
PDGFRA GeneProduct ensembl:ENSG00000134853
FLT1 GeneProduct ensembl:ENSG00000102755
STAT3 GeneProduct ensembl:ENSG00000168610
EGFR GeneProduct ensembl:ENSG00000146648
CAMK1 GeneProduct ensembl:ENSG00000134072
AKT1 GeneProduct ensembl:ENSG00000142208
MLST8 GeneProduct ensembl:ENSG00000167965
SQSTM1 GeneProduct ensembl:ENSG00000161011
MTOR GeneProduct ensembl:ENSG00000198793
RPTOR GeneProduct ensembl:ENSG00000141564
TSC1 GeneProduct ensembl:ENSG00000165699
p300 GeneProduct ensembl:ENSG00000100393
GRB10 GeneProduct ensembl:ENSG00000106070
PTEN GeneProduct ensembl:ENSG00000171862
GLUT1 GeneProduct ensembl:ENSG00000117394
VEGFA GeneProduct ensembl:ENSG00000112715
RHEB GeneProduct ensembl:ENSG00000106615
VHL GeneProduct ensembl:ENSG00000134086
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1B GeneProduct ensembl:ENSG00000143437
PBRM1 GeneProduct ensembl:ENSG00000163939
SETD2 GeneProduct ensembl:ENSG00000181555
BAP1 GeneProduct ensembl:ENSG00000163930
KDM5C GeneProduct ensembl:ENSG00000126012
TSC2 GeneProduct ensembl:ENSG00000103197
HIF1B GeneProduct ensembl:ENSG00000143437
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1A GeneProduct ensembl:ENSG00000100644
HIF1B GeneProduct ensembl:ENSG00000143437
HIF1A GeneProduct ensembl:ENSG00000100644
PDGFB GeneProduct ensembl:ENSG00000100311
TGFB1 GeneProduct ensembl:ENSG00000105329
TGFB2 GeneProduct ensembl:ENSG00000092969
TGFB3 GeneProduct ensembl:ENSG00000119699
CBP GeneProduct ensembl:ENSG00000005339
p300 GeneProduct ensembl:ENSG00000100393
CBP GeneProduct ensembl:ENSG00000005339
AKT1S1 GeneProduct ensembl:ENSG00000204673
ACACB GeneProduct ensembl:ENSG00000076555
ACLY GeneProduct ensembl:ENSG00000131473
MDH1 GeneProduct ensembl:ENSG00000014641
ME1 GeneProduct ensembl:ENSG00000065833
HK1 GeneProduct ensembl:ENSG00000156515
HK2 GeneProduct ensembl:ENSG00000159399
GPI GeneProduct ensembl:ENSG00000105220
PFKL GeneProduct ensembl:ENSG00000141959
PFKP GeneProduct ensembl:ENSG00000067057
PFKM GeneProduct ensembl:ENSG00000152556
ALDOA GeneProduct ensembl:ENSG00000149925
ALDOB GeneProduct ensembl:ENSG00000136872
ALDOC GeneProduct ensembl:ENSG00000109107
TPI1 GeneProduct ensembl:ENSG00000111669
GAPDH GeneProduct ensembl:ENSG00000111640
PGK1 GeneProduct ensembl:ENSG00000102144
PGK2 GeneProduct ensembl:ENSG00000170950
PGM1 GeneProduct ensembl:ENSG00000079739
PGM2 GeneProduct ensembl:ENSG00000169299
ENO1 GeneProduct ensembl:ENSG00000074800
ENO2 GeneProduct ensembl:ENSG00000111674
ENO3 GeneProduct ensembl:ENSG00000108515
PHGDH GeneProduct ensembl:ENSG00000092621
PSAT1 GeneProduct ensembl:ENSG00000135069
PSPH GeneProduct ensembl:ENSG00000146733
SHMT1 GeneProduct ensembl:ENSG00000176974
SHMT2 GeneProduct ensembl:ENSG00000182199
SDS GeneProduct ensembl:ENSG00000135094
SDSL GeneProduct ensembl:ENSG00000139410
PKLR GeneProduct ensembl:ENSG00000143627
LDHA GeneProduct ensembl:ENSG00000134333
LDHB GeneProduct ensembl:ENSG00000111716
LDHD GeneProduct ensembl:ENSG00000166816
LDHC GeneProduct ensembl:ENSG00000166796
PKM GeneProduct ensembl:ENSG00000067225
HIF1A GeneProduct ensembl:ENSG00000100644
PKM2 GeneProduct ensembl:ENSG00000067225
PDGFRB GeneProduct ensembl:ENSG00000113721
KDR GeneProduct ensembl:ENSG00000128052
BHLHE41 GeneProduct ensembl:ENSG00000123095
CDH13 GeneProduct ensembl:ENSG00000140945
CEP290 GeneProduct ensembl:ENSG00000198707
KSR1 GeneProduct ensembl:ENSG00000141068
PGBD5 GeneProduct ensembl:ENSG00000177614
PLOD2 GeneProduct ensembl:ENSG00000152952
SSPN GeneProduct ensembl:ENSG00000123096
RAPGEF5 GeneProduct ensembl:ENSG00000136237
ZEB1 GeneProduct ensembl:ENSG00000148516
TOX2 GeneProduct ensembl:ENSG00000124191
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References

  1. Dey N, Das F, Mariappan MM, Mandal CC, Ghosh-Choudhury N, Kasinath BS, et al. MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes. J Biol Chem. 2011 Jul 22;286(29):25586–603. PubMed Europe PMC Scholia
  2. Gao X, Wang H, Yang JJ, Liu X, Liu Z-R. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012 Mar 9;45(5):598–609. PubMed Europe PMC Scholia
  3. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013 Jul 4;499(7456):43–9. PubMed Europe PMC Scholia
  4. Demaria M, Poli V. PKM2, STAT3 and HIF-1α: The Warburg’s vicious circle. JAKSTAT. 2012 Jul 1;1(3):194–6. PubMed Europe PMC Scholia
  5. Von Roemeling CA, Marlow LA, Radisky DC, Rohl A, Larsen HE, Wei J, et al. Functional genomics identifies novel genes essential for clear cell renal cell carcinoma tumor cell proliferation and migration. Oncotarget. 2014 Jul 30;5(14):5320–34. PubMed Europe PMC Scholia
  6. Riazalhosseini Y, Lathrop M. Precision medicine from the renal cancer genome. Nat Rev Nephrol. 2016 Nov;12(11):655–66. PubMed Europe PMC Scholia
  7. Nargund AM, Pham CG, Dong Y, Wang PI, Osmangeyoglu HU, Xie Y, et al. The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma. Cell Rep. 2017 Mar 21;18(12):2893–906. PubMed Europe PMC Scholia
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