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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes
Open accessAbstract
Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
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“Interestingly, inactivating mutations and/or reduced expression of JmjC histone demethylases including JARID1C (Dalgliesh et al, 2010), UTX (van Haaften et al, 2009) and JHDM1B/FBXL10 (Frescas et al, 2007), occur in RCCs, multiple myeloma, glioblastoma multiforme and several other cancers.”
From The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases (2011) · cites this paper as Dalgliesh et al, 2010
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“A number of 2-oxoglutarate-dependent enzymes that act on chromatin are themselves targets of inactivating mutations in cancer, including the UTX H3K27 demethylase (also called KDM6A), JARID1C H3K4 demethylase (KDM5C), and TET2, making them attractive candidates for pathogenically relevant inhibition by succinate, fumarate, and R-2HG (Abdel-Wahab et al., 2009; Dalgliesh et al., 2010; Tefferi et al”
From Influence of Metabolism on Epigenetics and Disease (2013) · cites this paper as Dalgliesh et al., 2010
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H3K36 trimethylation-mediated biological functions in cancer
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“Inactivation of SETD2 by copy number loss and mutations has been reported as a common event in sporadic clear cell renal cell carcinoma (Dalgliesh et al., 2010; Duns et al., 2010; Cancer Genome Atlas Research Network, 2013; Hakimi et al., 2013; Sato et al., 2013).”
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BackgroundWhat can molecular pathology contribute to the management of renal cell carcinoma?
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Self-citationThe Chromatin Remodeling Gene ARID1A Is a New Prognostic Marker in Clear Cell Renal Cell Carcinoma
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“However, recent largescale sequencing screens of RCC revealed mutations in the histonemodifying genes ubiquitously transcribed tetratricopeptide repeat gene on x chromosome (UTX), set domain-containing protein 2 (SETD2) and lysinespecific demethylase 5C (KDM5C, JARID1C), and that loss of these genes correlated with…”
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“Other genes, such as SET domain containing protein 2 and Jumonji AT-rich interactive domain 1C have also been implicated, although at much lower frequency (3%) [15].”
BackgroundA global assessment of cancer genomic alterations in epigenetic mechanisms
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“The protein encoded by SETD2 is related to chromatin remodeling, and inactivating mutations of this gene are reported in clear cell renal cell carcinoma [34].”
Compendium of aberrant DNA methylation and histone modifications in cancer
Hattori, N., & Ushijima, T. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.140 · Cited by 72
A HIF-Regulated VHL-PTP1B-Src Signaling Axis Identifies a Therapeutic Target in Renal Cell Carcinoma
Suwaki, N., Vanhecke, E., Atkins, K. M., Graf, M., Swabey, K., Huang, P. H., Schraml, P., Moch, H., Mulick, A. R., Brewer, D. S., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002004 · Cited by 66
SETD2 histone modifier loss in aggressive GI stromal tumours
Huang, K. K., McPherson, J. R., Tay, S. T., Das, K., Tan, I. B., Ng, C. C. Y., Chia, N., Zhang, S. L., Myint, S. S., Hu, L., et al. (2015) · Gut · doi:10.1136/gutjnl-2015-309482 · Cited by 68
Self-citationPBRM1, SETD2 and BAP1 — the trinity of 3p in clear cell renal cell carcinoma
Walton, J., Lawson, K. A., Prinos, P., Finelli, A., Arrowsmith, C. H., & Ailles, L. (2022) · Nature Reviews Urology · doi:10.1038/s41585-022-00659-1 · Cited by 74
NCG 4.0: the network of cancer genes in the era of massive mutational screenings of cancer genomes
An, Ö., Pendino, V., D’Antonio, M., Ratti, E., Gentilini, M., & Ciccarelli, F. D. (2014) · Database · doi:10.1093/database/bau015 · Cited by 63
Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism
Pollard, P. J., Yang, M. H., Su, H., Soga, T., & Kranc, K. R. (2014) · Hypoxia · doi:10.2147/hp.s47968 · Cited by 67
“Inactivating mutations in JARID1C were identified in ccRCC, together with the histone H3 lysine 36 methyltransferase SET domain containing 2.(146) The evidence highlights the importance of chromatin modifying enzymes in cancer regulation.”
BackgroundQin, Y., Deng, Y., Ricketts, C. J., Srikantan, S., Wang, E., Maher, E. R., & Dahia, P. L. M. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt638 · Cited by 64
Brier, A.-S. B., Loft, A., Madsen, J. G. S., Rosengren, T., Nielsen, R., Schmidt, S. F., Liu, Z. Z., Yan, Q., Gronemeyer, H., & Mandrup, S. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1156 · Cited by 63
“Multiple studies of KDM5A (11–14) and KDM5B (15–18) have reported an involvement of these in cancer, and some studies of KDM5C (19,20) and KDM5D (9) indicate that this could be a common feature of all KDM5 family members.”
BackgroundEpigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma
Mehdi, A., & Riazalhosseini, Y. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081774 · Cited by 68
“Moreover, most mutations in SETD2 and KDM5C also occur in a mutually exclusive manner [28,118].”
BackgroundAdjuvant Therapy for Renal Cell Carcinoma: Past, Present, and Future
Pal, S. K., & Haas, N. B. (2014) · The Oncologist · doi:10.1634/theoncologist.2014-0105 · Cited by 63
He, X., Sun, F., Guo, F., Wang, K., Gao, Y., Feng, Y., Song, B., Li, W., & Yang, L. (2017) · Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics · doi:10.3727/096504016x14719078133203 · Cited by 63
Clonal architectures predict clinical outcome in clear cell renal cell carcinoma
Huang, Y. F., Wang, J., Jia, P., Li, X., Pei, G., Wang, C., Fang, X., Zhao, Z., Cai, Z., Yi, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09241-7 · Cited by 66
Li, X., Li, Q., Ju, L., Zhao, C. N., Zhao, L., Du, J., Wang, Y., Zheng, L., Song, B., Li, L., et al. (2020) · Hepatology · doi:10.1002/hep.31594 · Cited by 62
Shen, H., Zhang, W., Huang, Y., He, Y., Hu, G.-S., Wang, L., Peng, B., Jia, Y., Li, T., Rong, R., et al. (2021) · Advanced Science · doi:10.1002/advs.202004635 · Cited by 66
da Costa, W. H., Rezende, M. T., Carneiro, F. C., Rocha, R. M., da Cunha, I. W., Carraro, D. M., Guimarães, G. C., & Zéqui, S. D. C. (2013) · British Journal of Urology · doi:10.1111/bju.12426 · Cited by 63
Audenet, F., Yates, D. R., Cancel‐Tassin, G., Cussenot, O., & Morgan Rouprêt, A. (2011) · British Journal of Urology · doi:10.1111/j.1464-410x.2011.10661.x · Cited by 63
Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation
Zhang, Y.-L., Sun, J.-W., Xie, Y.-Y., Zhou, Y., Liu, P., Song, J.-C., Xu, C., Wang, L., Liu, D., Xu, A., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0015-9 · Cited by 67
UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma
Li, X., Zhang, Y., Zheng, L., Liu, M., Chen, C. D., & Jiang, H. (2018) · Nature Communications · doi:10.1038/s41467-018-05084-w · Cited by 63
Merlin/ERM proteins establish cortical asymmetry and centrosome positionPreprint
Hebert, A. M., DuBoff, B., Casaletto, J. B., Gladden, A. B., & McClatchey, A. I. (2012) · Genes & Development · doi:10.1101/gad.194027.112 · Cited by 70
“…number of sporadic malignant human cancers, including mesothelioma and renal adenocarcinoma, both of which are often aneuploid (Musti et al. 2006; Dalgliesh et al. 2010); in fact, we found that NF2-deficient mesothelioma cells exhibit defective centrosome clustering and multipolar spindle…”
BackgroundRole of H3K27 Demethylases Jmjd3 and UTX in Transcriptional RegulationPreprint
Hübner, M. R., & Spector, D. L. (2010) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2010.75.020 · Cited by 65
D’Aniello, C., Berretta, M., Cavaliere, C., Rossetti, S., Facchini, B. A., Iovane, G., Mollo, G., Capasso, M., Pepa, C. D., Pesce, L., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01400 · Cited by 64
“, in genes involved in the VEGF pathway) that are associated with the risk of RCC (69, 70) as well as with RR and adverse events in patients receiving TTs.”
BackgroundTargeting Epigenetic Regulators with Covalent Small-Molecule Inhibitors
Zhang, Y., Rong, D., Li, B., & Wang, Y. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02055 · Cited by 63
New Insights into the Biology of Renal Cell Carcinoma
Li, L., & Kaelin, W. G. (2011) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2011.04.004 · Cited by 63
“as KDM5C) histone demethylase, and the UTX (also known as KMD6A) histone demethylase, are sometimes mutated in clear-cell RCC.(14)”
BackgroundDynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma
Tiedemann, R. L., Hlady, R. A., Hanavan, P. D., Lake, D. F., Tibes, R., Lee, J., Choi, J.-H., Ho, T. H., & Robertson, K. D. (2015) · Oncotarget · doi:10.18632/oncotarget.6481 · Cited by 66
“RAS, BRAF, TP53, RB) are largely absent [2-5], and ccRCC is tightly linked to a distinct transcriptional signature due to inactivation of the VHL gene, which is mediated in part through deregulation of the epigenome [6].”
BackgroundMolecular basis for substrate recognition by lysine methyltransferases and demethylases
Rizzo, P. A. D., & Trievel, R. C. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.06.008 · Cited by 61
Targeting the epigenome for treatment of cancer
Geutjes, E.-J., Bajpe, P. K., & Bernards, R. (2011) · Oncogene · doi:10.1038/onc.2011.552 · Cited by 62
“…et al., 2011) KDM6A Histone H3K27 demethylase Lymphoma, renal cell carcinoma and bladder carcinoma Inactivating mutations (van Haaften et al., 2009; Dalgliesh et al., 2010; Gui et al., 2011; Varela et al., 2011; Wartman et al., 2011) Oncogene excluding imprinted loci and the inactive…”
BackgroundInfluentialTargets in Epigenetics: Inhibiting the Methyl Writers of the Histone Code
Yost, J. M., Korboukh, I., Liu, F., Gao, C., & Jin, J. J. (2011) · Current Chemical Genomics · doi:10.2174/1875397301005010072 · Cited by 61
Gonçalves, T. F., Gonçalves, A. P., Rodrigues, N. F., dos Santos, J. M., Pimentel, M. M. G., & Santos-Rebouças, C. B. (2014) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2014.02.011 · Cited by 61
Liu, W., Li, C., Xu, Y., Yang, H., Yao, Q., Han, J., Shang, D., Zhang, C., Su, F., Li, X., et al. (2013) · Bioinformatics · doi:10.1093/bioinformatics/btt373 · Cited by 61
van Vlodrop, I. J. H., Joosten, S. C., Meyer, T. D., Smits, K. M., Neste, L. V., Melotte, V., Baldewijns, M. M. L. L., Schouten, L. J., van den Brandt, P. A., Jeschke, J., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1236 · Cited by 61
“To increase the possibility of the identification of (renal cell) cancer-specific genes, we focused on candidates involved in DNA repair, angiogenesis and hypoxia, carbohydrate metabolism, the TGFb or Notch pathway based on Gene Ontology (GO) terms, and genes known to be mutated in RCC (11, 16) or frequently mutated i…”
BackgroundRegulating Methylation at H3K27: A Trick or Treat for Cancer Cell Plasticity
Das, P., & Taube, J. H. (2020) · Cancers · doi:10.3390/cancers12102792 · Cited by 61
“Loss-of function mutations and deletions targeting KDM6A have been reported in medulloblastoma [178], T-cell acute lymphoblastic leukemia (T-ALL) [175,176], acute lymphoblastic leukemia (ALL) [175,179], renal cell carcinoma [180], bladder cancer [181,182], chronic myelomonocytic leukemia (CMML) [153], multiple melanom…”
BackgroundCholesterol and the development of clear-cell renal carcinoma
Drabkin, H. A., & Gemmill, R. M. (2012) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2012.08.002 · Cited by 61
Arseneault, M., Monlong, J., Vasudev, N. S., Laskar, R. S., Safisamghabadi, M., Harnden, P., Egevad, L., Nourbehesht, N., Panichnantakul, P., Holcátová, I., et al. (2017) · Scientific Reports · doi:10.1038/srep44876 · Cited by 59
“Mutations of KDM6A leading to its inactivation have been recurrently observed in ccRCC 8,23 , highlighting this gene as a potential key tumor suppressor in renal cancer.”
SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12
González-Rodríguez, P., Engskog‐Vlachos, P., Zhang, H., Murgoci, A., Zerdes, I., & Joseph, B. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2266-x · Cited by 65
Epidemiology, Aetiology, and Pathogenesis of Renal Cell Carcinoma
Protzel, C., Maruschke, M., & Hakenberg, O. W. (2012) · European Urology Supplements · doi:10.1016/j.eursup.2012.05.002 · Cited by 61
“Other frequently mutated genes in RCC are RAS, BRAF, p53, pRB (retinoblastoma), cyclin-dependent kinase inhibitor 2A (CDKN2A), PTEN, and ERBB2 [53,55].”
Background
Metadata
- Authors
- Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P. J., Forbes, S., Jia, M., Jones, D., Knott, H., Kok, C. Y., Lau, K. W., Leroy, C., Lin, M.-L., McBride, D. J., Maddison, M., Maguire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., O’Meara, S., Pleasance, E., Rajasingham, A., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P. S., Turrell, K., Dykema, K. J., Khoo, S. K., Petillo, D., Wondergem, B., Anema, J., Kahnoski, R. J., Teh, B. T., Stratton, M. R., & Futreal, P. A.
- Affiliations
- Wellcome Sanger Institute (GB)
- Van Andel Institute (US)
- Spectrum Health (US)
- Institute of Cancer Research (GB)
- Corresponding author
- Teh, Bin Tean
- Stratton, Michael R.
- Futreal, P. Andrew
- ORCID
- Dalgliesh, Gillian L.
- Greenman, Chris
- Chen, Lina
- Davies, Helen
- Edkins, Sarah
- Latimer, Calli
- Teague, Jon
- Barthorpe, Syd
- Buck, Gemma
- Campbell, Peter J.
- Jia, Mingming
- Jones, David
- Lau, King Wai
- Lin, Meng-Lay
- McBride, David J.
- Menzies, Andrew
- Mironenko, Tatiana
- Pleasance, Erin
- Shepherd, Rebecca
- Tarpey, Patrick S.
- Khoo, Sok Kean
- Petillo, David
- Kahnoski, Richard J.
- Teh, Bin Tean
- Stratton, Michael R.
- Futreal, P. Andrew
- Venue
- Nature
- Published
- 2010-01
- Volume
- 463
- Issue
- 7279
- Pages
- 360-363
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2820242
- OpenAlex
- W2079212177
- Cited by
- 1,173
- References
- 28
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 33 · 2023: 43 · 2022: 40 · 2021: 58 · 2020: 63 · 2019: 54 · 2018: 66 · 2017: 65 · 2016: 91 · 2015: 85 · 2014: 119 · 2013: 125 · 2012: 114
- FWCI
- 109.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (077012/Z/05/Z, 082359, 077012, 088340, 093867)
- Topics
- Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- clear cell renal cell carcinoma, somatic mutations, histone-modifying enzymes, SETD2, JARID1C, KDM6A, neurofibromatosis type 2, VHL, chromatin modification, histone H3 lysine 36 methylation, histone H3 lysine 4 demethylation, tumor suppressor, cancer gene identification
- MeSH terms
- Carcinoma, Renal Cell, Chromatin, Histones, Humans, Kidney Neoplasms, Mutation, Nuclear Proteins, Oxidoreductases, N-Demethylating, Histone-Lysine N-Methyltransferase, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Genes, Neurofibromatosis 2, Sequence Analysis, DNA, Histone Demethylases
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