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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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“training dataset in cross-dataset experiment: GSE10072 for lung cancer [40], GSE13911 for stomach cancer [41], GSE17856 for liver cancer [42], GSE5364 for thyroid cancer [42], GSE15641 and GSE17895 for kidney cancer [43], [44], GSE3494 and GSE1456 for breast cancer [34], [45],”
MethodMutational heterogeneity between different regional tumour grades of clear cell renal cell carcinoma
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SETD2 — linking stem cell survival and transformation
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“UTX is one of the genes frequently mutated in clear cell renal cell carcinoma (ccRCC) [28,37] and therefore to investigate UTX transcriptional regulation further, we used a ccRCC line 786-O for disruption and re-expression of UTX in this study.”
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“…inactivation of the VHL tumor suppressor gene on a background of a loss of chromosome 3p is an important genetic event in most ccRCCs. 10 , 11 12-14 Importantly, these most commonly mutated genes were associated with variations in the TME and affected the effec-tiveness of immunotherapeutic…”
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“In some of the studies, matched normal-tumor pairs were utilized to identify germline and rare somatic mutations [4,6,7], while in other studies, matched tumor-tumor (e.”
BackgroundResultSelf-citationGenome-Based Multi-targeting of Cancer: Hype or Hope?
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“For example, the histones HIST1H3B, H3F3A, DNMT1, and TET1 covalently modify DNA, E2H2, SETD2, and KDM6A, which in turn methylate or demethylate histones (Delhommeau et al. 2009; Schwartzentruber et al. 2012; Wu et al. 2012; Ley et al. 2010; Dalgliesh et al. 2010).”
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“…melanoma (Adelaide et al., 1988), stomach (Ikeda et al., 2008) and ovarian cancer (Schmitt et al., 1996; Mayr et al., 2006); ITGA11 in kidney (Dalgliesh et al., 2010), laryngeal (Stransky et al., 2011) and lung (Young et al., 2009); MHC class ll alpha chain in non-small cell lung carcinoma…”
BackgroundZebrafish as a model for von Hippel Lindau and hypoxia-inducible factor signaling
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GENETIC SYNDROMES ASSOCIATED WITH RENAL CELL CARCINOMA - A REVIEW
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Alterations of Histone Modifications in Cancer
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“It has been reported that SETD2 mutations were more frequently found in the hypoxic group of kidney tumors (65, 66), and the hypoxic group of HCC also had more patients with mutant SETD2 in our study (Figures 5B, C).”
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Nucleosome Occupancy and Gene Regulation During Tumorigenesis
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Sunitinib as a paradigm for tyrosine kinase inhibitor development for renal cell carcinoma
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“Gene expression analysis of ccRCC has identified a pseudohypoxic phenotype [6], in which loss of VHL mimics the gene expression associated with the hypoxic response, suggesting that the VHL-HIF-VEGF-VEGF receptor (VEGFR) cascade is critical for ccRCC pathogenesis.”
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InfluentialCho, D. (2013) · OncoTargets and Therapy · doi:10.2147/ott.s45872 · Cited by 8
“Likewise, SETD2, which encodes a histone methyltransferase, is mutated in approximately 8% of clear cell renal cell carcinomas.(34) Not surprisingly, correlation of the presence of these mutations with clinical outcomes is already providing prognostic information.”
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“…above, UTX (KDM6A, reviewed in (Van der Meulen et al., 2014)) mutations have been found in a substantial percentage of clear cell renal cell cancer (Dalgliesh et al., 2010), bladder cancer (Gui et al., 2011), prostate cancer (Lindberg et al., 2013), and medulloblastoma (Dubuc et al., 2013; Pugh et…”
BackgroundCancer genomics and pathology: All Together Now
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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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