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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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DNA methylation modifications induced by hexavalent chromium
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Yang, L., Wang, X., Liu, J., Liu, X., Li, S., Zheng, F., Dong, Q., Xu, S., Xiong, J., & Fu, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1225023 · Cited by 22
“Current studies have shown that epigenetic aberrations are common in RCC, especially histone modifications, and are closely associated with their prognosis and treatment (22, 23).”
BackgroundFaulty Epithelial Polarity Genes and Cancer
Tervonen, T. A., Partanen, J. I., Saarikoski, S. T., Myllynen, M., Marques, E., Paasonen, K., Moilanen, A., Wohlfahrt, G., Kovanen, P. E., & Klefström, J. T. (2011) · Advances in cancer research · doi:10.1016/b978-0-12-385524-4.00003-9 · Cited by 24
Promises and challenges of anticancer drugs that target the epigenome
Verbrugge, I., Johnstone, R. W., & Bots, M. L. (2011) · Epigenomics · doi:10.2217/epi.11.82 · Cited by 22
Liang, Z., Diamond, M., Smith, J. A., Schnell, M. J., & Daniel, R. (2011) · Epigenetics & Chromatin · doi:10.1186/1756-8935-4-18 · Cited by 22
“In addition, SMCX levels were found to be increased in prostate and seminoma cancers and to be absent in renal carcinomas [24,25].”
BackgroundTumor Suppressor NF2/Merlin Is a Microtubule Stabilizer
Smole, Z., Thoma, C. R., Applegate, K. T., Duda, M., Gutbrodt, K. L., Danuser, G. M., & Krek, W. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-1334 · Cited by 22
“NF2 tumor suppressor is also dysfunctional in diverse non-nervous malignancies such as mesotheliomas (12), colorectal cancer (13), melanomas (14) and ccRCC (10).”
BackgroundProminent role of histone lysine demethylases in cancer epigenetics and therapy
Janardhan, A., Kathera, C., Darsi, A., Ali, W., He, L., Yang, Y., Luo, L., & Guo, Z. (2018) · Oncotarget · doi:10.18632/oncotarget.24319 · Cited by 23
“In the other side recurrent mutations in genes that encodes histone demethylases have been discovered in the gene encoding ubiquitously transcribed TPR protein on the X chromosome, where inactivating mutations are present in various types of tumors [116, 117], indicating the role of lysine methylases in human tumorige…”
BackgroundWi, Y. C., Moon, A., Jung, M.-J., Kim, Y., Bang, S., Jang, K., Paik, S. S., & Shin, S. (2018) · Journal of Pathology and Translational Medicine · doi:10.4132/jptm.2018.09.21 · Cited by 22
“TNBC is generally considered an individual subtype of breast cancer, but it is also a highly heterogeneous disease which consists of various subgroups of tumors with different molecular, histologic, and clinical characteristics.(2) Advances in endocrine therapy and HER2-targeted therapy have greatly improved the survi…”
BackgroundResultInfluentialChakraborty, A. A. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.03.012 · Cited by 23
Senescence-associated protein p400 is a prognostic marker in renal cell carcinoma
Macher‐Goeppinger, S., Bermejo, J. L., Schirmacher, P., Pahernik, S. A., Hohenfellner, M., & Roth, W. (2013) · Oncology Reports · doi:10.3892/or.2013.2698 · Cited by 23
Suffocating cancer: hypoxia-associated epimutations as targets for cancer therapy
Thirlwell, C., Schulz, L., Dibra, H. K., & Beck, S. (2011) · Clinical Epigenetics · doi:10.1186/1868-7083-3-9 · Cited by 22
Broncy, L., Njima, B. B., Méjean, A., Béroud, C., Romdhane, K. B., Ilié, M., Hofman, V., Muret, J. C., Hofman, P. M., Chaabouni-Bouhamed, H., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.25102 · Cited by 22
Advances and Opportunities in Epigenetic Chemical Biology
Beyer, J. N., Raniszewski, N. R., & Burslem, G. M. (2020) · ChemBioChem · doi:10.1002/cbic.202000459 · Cited by 23
Complex role of HIF in cancer: the known, the unknown, and the unexpected
Huang, E. L., Tiburcio, P. D. B., & Choi, H. (2014) · Hypoxia · doi:10.2147/hp.s50651 · Cited by 20
“63 Furthermore, rare somatic, loss-of-function HIF1A mutations have been identified in the specimens of clear-cell renal carcinoma, 64,65 and common focal, homozygous deletions have been detected in cell lines of VHL-deficient renal cell carcinomas.”
DNA mismatch repair in the context of chromatin
Huang, Y., & Li, G. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-0379-7 · Cited by 21
Chemical Biology of Lysine Demethylases
Heightman, T. D. (2011) · Current Chemical Genomics · doi:10.2174/1875397301005010062 · Cited by 21
“…loss of function resulted in decreased expression of metabolically active genes (e.g. peroxisome proliferator–activated receptor- and medium-chain acyl-CoA dehydrogenase) in skeletal muscle, and impaired expression of cold-induced uncoupling protein 1 in brown adipose tissue in rodents [28].”
BackgroundOngoing challenges in the treatment of adenoid cystic carcinoma of the head and neck
Subramaniam, T., Lennon, P., & O'Neill, J. P. (2015) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-015-1298-1 · Cited by 21
“Multiple aberrations were also noted in the actin dependent regulator of chromatin (SMARC) family [24], that are known to have a role in development of malignant disease [26, 27].”
BackgroundRosen, M. D., Chan, I. H., & Privalsky, M. L. (2011) · Molecular Endocrinology · doi:10.1210/me.2010-0420 · Cited by 21
Thapa, R. J., Chen, P., Cheung, M., Nogusa, S., Pei, J., Peri, S., Testa, J. R., & Balachandran, S. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-1010 · Cited by 21
“It is noteworthy that VHL mutations on average are found to only occur in approximately half of all ccRCC samples (with a range of ~20% to >70%, depending on the study), so unmutated VHL in all three RCC cell lines is not a statistical improbability (28-31).”
Tumor suppression by the histone demethylase UTX
Tsai, M.-C., Wang, J. K., & Chang, H. Y. (2010) · Cell Cycle · doi:10.4161/cc.9.11.11845 · Cited by 21
Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma
Pham, D.-X., & Hsu, T. (2025) · Journal of Biomedical Science · doi:10.1186/s12929-024-01111-9 · Cited by 25
Molecular Markers to Predict Response to Therapy
García-Donás, J., Rodríguez‐Antona, C., & Jonasch, E. W. (2013) · Seminars in Oncology · doi:10.1053/j.seminoncol.2013.05.005 · Cited by 20
Kristensen, J. B. L., Nielsen, A. L., Jørgensen, L. M., Kristensen, L. H., Helgstrand, C., Juknaitė, L., Kristensen, J. L., Kastrup, J. S., Clausen, R. P., Olsen, L., et al. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.05.023 · Cited by 20
Gowrishankar, B., Przybycin, C. G., Ma, C., Nandula, S. V., Rini, B. I., Campbell, S. C., Klein, E. A., Chaganti, R. S. K., Magi‐Galluzzi, C., & Houldsworth, J. (2014) · The Journal of Urology · doi:10.1016/j.juro.2014.11.099 · Cited by 20
Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment
Baudoin, N. C., & Bloomfield, M. (2021) · Genes · doi:10.3390/genes12040558 · Cited by 20
The emerging roles of histone demethylases in cancers
Tong, D., Tang, Y., & Zhong, P. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-023-10160-9 · Cited by 20
“Aberrant mutation of the KDM5C gene was observed in renal carcinoma [149].”
Mulji, A., Haslam, C. P., Brown, F., Randle, R. A., Karamshi, B., Smith, J. E., Eagle, R., Muñoz, J. A., Taylor, J., Sheikh, A., et al. (2012) · SLAS DISCOVERY · doi:10.1177/1087057111418229 · Cited by 20
Setting and resetting of epigenetic marks in malignant transformation and development
Richly, H., Lange, M., Simboeck, E., & Croce, L. D. (2010) · BioEssays · doi:10.1002/bies.201000016 · Cited by 20
“With the identification and characterization of histone modifying enzymes (such as HDACs and DNMTs), we now have the possibility to study not only the biochemical characteristics of those enzymes but also the associated interacting proteins, in both normal and pathological scenarios [103].”
Tumor suppressive activity of prolyl isomerase Pin1 in renal cell carcinoma
Teng, B. L., Hacker, K. E., Chen, S., Means, A. R., & Rathmell, W. K. (2011) · Molecular Oncology · doi:10.1016/j.molonc.2011.06.002 · Cited by 20
“In particular, although p53 is commonly mutated in many human cancers, p53 mutation is infrequent in renal cell carcinoma (RCC) (Dalgliesh et al., 2010; Gurova et al., 2004).”
BackgroundMethod
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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