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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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“The altered genes include PBRM1, involved in chromatin remodeling; BAP1, a histone deubiquitinase; and SETD2, a histone methyltransferase (8).”
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BackgroundPrognostic value of UTX expression in patients with clear cell renal cell carcinoma
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BackgroundSETD2 loss sensitizes cells to PI3Kβ and AKT inhibition
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“Recent advances in DNA‐sequencing techniques have shown that genes coding for proteins involved in the regulation of chromatin remodeling and histone methylation are frequently mutated and closely linked with tumor progression (14,27).”
BackgroundSelf-citationQuaas, A., Rahvar, A., Burdelski, C. M., Koop, C., Eichelberg, C., Rink, M., Dahlem, R., Schlomm, T., Tsourlakis, M. C., Simon, R., et al. (2014) · World Journal of Urology · doi:10.1007/s00345-014-1463-6 · Cited by 14
“The von Hippel–Lindau (VHL) gene, which is mutated and/or inactivated by chromosomal deletion in more than 50 % of clear cell cancers [33] and silenced by promoter hypermethylation in another 10–15 % of ccRCC [34], is a known key regulator of microtubule dynamics [35].”
BackgroundHistone Demethylases in Cancer
Sainathan, S. K., Paul, S., Ramalingam, S., Baranda, J. C., Anant, S., & Dhar, A. (2015) · Current Pharmacology Reports · doi:10.1007/s40495-015-0025-y · Cited by 14
Park, K. C., Heo, J. H., Jeon, J. Y., Choi, H. J., Jo, A., Kim, S. W., Kwon, H. J., Hong, S. J., & Han, K. S. (2015) · BMC Cancer · doi:10.1186/s12885-014-1003-1 · Cited by 14
“A high-throughput gene study involving solution capture and sequencing of the coding exons of 20,000 protein-coding genes identified new cancer loci, including genes encoding enzymes that demethylate/methylate key lysine residues in histone H3, which is implicated in transcriptional control by regulating chromatin str…”
BackgroundSETD2 reduction adversely affects the development of mouse early embryos
Li, C., Huang, Z., & Gu, L. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29325 · Cited by 14
Expression and Prognostic Significance of EP300, TP53 and BAX in Clear Cell Renal Cell Carcinoma
Godlewski, J., Kraziński, B. E., Kowalczyk, A. E., Kiewisz, J., Kieżun, J., Kwiatkowski, P., Śliwińska-Jewsiewicka, A., Wierzbicki, P., & Kmieć, Z. (2017) · Anticancer Research · doi:10.21873/anticanres.11646 · Cited by 14
Meet Me Halfway: When Genomics Meets Structural Bioinformatics
Gong, S., Worth, C. L., Cheng, T. M. K., & Blundell, T. L. (2011) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-011-9259-1 · Cited by 15
LRRK2 is a candidate prognostic biomarker for clear cell renal cell carcinoma
Yang, C., Pang, J., Xu, J., Pan, H., Li, Y., Zhang, H., Liu, H., & Xiao, S. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02047-y · Cited by 13
Ikram, M., Singh, S., Ansari, M. J., Islam, J., Shariq, M., Alharbi, R. S., Siddiqui, M. A., Tan, C. S., Sayyed, R. Z., & Alahmadi, T. A. (2023) · Journal of King Saud University - Science · doi:10.1016/j.jksus.2023.102911 · Cited by 13
Expression analysis of the estrogen receptor target genes in renal cell carcinoma
Liu, Z., Lü, Y., He, Z., Chen, L., & Lu, Y. (2014) · Molecular Medicine Reports · doi:10.3892/mmr.2014.2766 · Cited by 13
“Inactivated SET domain, bifurcated 1 and lysine‑specific demethylase C, which are involved in histone modification, has been identified by sequencing in a previous study (9).”
Self-citationPeri, S., Caretti, E., Tricarico, R., Devarajan, K., Cheung, M., Sementino, E., Menges, C. W., Nicolas, É., Vanderveer, L., Howard, S., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12192 · Cited by 13
“Each change is pathogenic and previously reported in ccRCC or pheochromocytomas [26-29].”
BackgroundSETD2 as a regulator of N6-methyladenosine RNA methylation and modifiers in cancer
Kumari, S., & Muthusamy, S. (2020) · European Journal of Cancer Prevention · doi:10.1097/cej.0000000000000587 · Cited by 15
“SETD2 is involved in DNA mismatch repair (in mammals, H3K36m3 recruits hMutSα to the chromatin and interacts with the PWWP domain of hMSH6) (Li et al., 2013), homologous recombination (brought about by Lens Epithelium-Derived Growth Factor), DNA methylation (H3K36me3 binding of DNMT3B) (Dhayalan et al., 2010) and nucl…”
BackgroundSong, J., Du, L., Liu, P., Wang, F., Zhang, B., Xie, Y., Lu, J., Jin, Y., Zhou, Y., Lv, G., et al. (2021) · 癌症：英文版 · doi:10.1002/cac2.12189 · Cited by 12
“SETD2mutations are frequently detected in solid tumors [14, 41] and leukemias [42–45], and contribute to chemotherapeutic resistance [46, 47].”
BackgroundMa, T., Wang, X., Wang, J., Liu, X., Lai, S., Zhang, W., Meng, L., Tian, Z., & Zhang, Y. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.726369 · Cited by 13
“To validate the expression of target lncRNAs, we extracted gene expression profile data from four datasets with more than 60 ccRCC samples in the Gene Expression Omnibus (GEO) database, including GSE17895 (tumor: n 151, normal: n 9), GSE40435 (tumor: n 101, normal: n 101), GSE46699 (tumor: n 67, normal: n 63), and GSE…”
MethodGutenberg, A., Nischwitz, M., Gunawan, B., Enders, C., Jung, K., Bergmann, M., Feiden, W., Egensperger, R., Keyvani, K., Stolke, D., et al. (2014) · Cancer Genetics · doi:10.1016/j.cancergen.2014.05.004 · Cited by 13
Loss of CDC14B Expression in Clear Cell Renal Cell Carcinoma
Kim, Y., Choi, J.-W., Lee, J. H., & Kim, Y. (2014) · American Journal of Clinical Pathology · doi:10.1309/ajcp4pe4jpsrgbqs · Cited by 13
Histone Demethylase Gene PHF2 Is Mutated in Gastric and Colorectal Cancers
Lee, J. H., Yoo, N. J., Kim, M. S., & Lee, S. H. (2016) · Pathology & Oncology Research · doi:10.1007/s12253-016-0130-1 · Cited by 13
Bivalent Regulation and Related Mechanisms of H3K4/27/9me3 in Stem Cells
Sun, H., Wang, Y., Wang, Y., Ji, F., Wang, A., Yang, M., He, X., & Li, L. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10234-7 · Cited by 12
A new horizon for epigenetic medicine?
Chen, S., & Shi, Y. (2012) · Cell Research · doi:10.1038/cr.2012.136 · Cited by 13
The Role of the PAX Genes in Renal Cell Carcinoma
Li, L., Hossain, S. M., & Eccles, M. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126730 · Cited by 11
“Frequently mutated genes include those regulating the cellular oxygen pathway (e.g., VHL ) and maintaining chromatin structure integrity (e.g., PBRM1 and BAP1 ) [64,65].”
BackgroundMondal, V., Higgins, P. J., & Samarakoon, R. (2024) · Cancers · doi:10.3390/cancers16152758 · Cited by 16
“Whole genome sequencing of primary RCC tumors and cell lines revealed that about 33% of VHL wild-type clear cell RCC had mutations in the NF2 tumor suppressor gene [45].”
BackgroundNew players in the landscape of renal cell carcinoma bone metastasis and therapeutic opportunities
Cesana, B., Cochet, C., & Filhol, O. (2024) · International Journal of Cancer · doi:10.1002/ijc.35181 · Cited by 13
A New Frontier in Personalized Cancer Therapy: Mapping Molecular Changes
Kasaian, K., & Jones, S. J. M. (2011) · Future Oncology · doi:10.2217/fon.11.63 · Cited by 12
Renal Cell Carcinoma Deep Sequencing: Recent Developments
Farber, L. J., Furge, K., & Teh, B. T. (2012) · Current Oncology Reports · doi:10.1007/s11912-012-0230-3 · Cited by 12
Self-citationO’Mahony, F. C., Nanda, J., Laird, A., Mullen, P., Caldwell, H., Overton, I. M., Eöry, L., O’Donnell, M., Faratian, D., Powles, T. B., et al. (2013) · Journal of Visualized Experiments · doi:10.3791/50221 · Cited by 11
Remarkable difference of somatic mutation patterns between oncogenes and tumor suppressor genes
Tian, D. (2011) · Oncology Reports · doi:10.3892/or.2011.1443 · Cited by 12
“As the sequencing method becoming cheaper and easier, many large-scale studies have been published identifying mutations both in coding regions and in whole genome of human tumors (6-12).”
Nicotine induces alteration of H3K27 demethylase UTX in kidney cancer cell
Guo, X., Li, X., Wang, Y., Tian, Z., Duan, X., & Cai, Z. (2013) · Human & Experimental Toxicology · doi:10.1177/0960327113499043 · Cited by 12
“Till date, several demethylases such as JARIDIC and UTX have been indentified inactivating mutations in RCC.(23) Our previous study has also indicated an association between the H3K9 demethylase JMJD1A and RCC.”
BackgroundXie, J., Zhu, C., Wu, J., Li, C., Luo, L., Xia, L., Li, X., Gui, Y., Cai, Z., & Li, Z. (2016) · Oncotarget · doi:10.18632/oncotarget.6829 · Cited by 12
“Due to recent sequencing efforts have identified frequent mutations of chromatin remodeling and histonemodifying genes in ccRCC [12, 14, 30], we analyzed whether C12orf59 expression is associated with the mutation status of these genes (Supplementary Table S5).”
BackgroundMLL2 protein is a prognostic marker for gastrointestinal diffuse large B-cell lymphoma.
Ye, H., Lu, L., Ge, B., Gao, S., Ma, Y., Liang, B., Yu, K., & Yang, K. (2015) · PubMed Central · Cited by 12
Seah, C. S., Kasim, S. B., Fudzee, M. F. M., Ping, J. M. L. T., Mohamad, M. S., Saedudin, R. R., & Ismail, M. A. (2017) · Saudi Journal of Biological Sciences · doi:10.1016/j.sjbs.2017.11.024 · Cited by 12
“Thyroid Cancer Dataset (Yu et al., 2008) (Dalgliesh et al., 2010): The GEO ID of chosen kidney cancer dataset is GSE17895.”
BackgroundWang, M., Cao, Y., Xia, M., Al‐Hatmi, A. M. S., Ou, W., Wang, Y., Sibirny, A. А., Zhao, L., Zou, C., Liao, W., et al. (2019) · Yeast · doi:10.1002/yea.3397 · Cited by 12
“In mice died 2 months after inoculation, obviously non‐invasive urothelial carcinoma was observed (Dalgliesh et al., 2010), a disease associated with tuberous sclerosis that can result in kidney cancer (Kapoor, Sikri, Grover, Malhotra, & Sachdeva, 2014; Ramirez‐Garcia et al., 2016).”
BackgroundKhoury, L. Y. E., Fu, S., Hlady, R. A., Wagner, R. T., Wang, L., Eckel‐Passow, J. E., Castle, E. P., Stanton, M., Thompson, R. H., Parker, A. S., et al. (2021) · Clinical Epigenetics · doi:10.1186/s13148-020-00998-z · Cited by 14
The Circular RNA circXPO1 Promotes Tumor Growth via Sponging MicroRNA-23a in Prostate Carcinoma
Chen, H., Zhang, P., Yu, B., & Liu, J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.712145 · Cited by 12
“MiR-23a acts as an oncogene in pancreatic carcinoma by targeting FOXP2 (26) and promotes tumor progression by targeting SETD2 in various carcinoma (27).”
BackgroundHo, T. H., Nateras, R. N., Yan, H., Park, J. G., Jensen, S., Borges, C. R., Lee, J., Champion, M. D., Tibes, R., Bryce, A. H., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132831 · Cited by 12
New cancer targets emerging from studies of the Von Hippel‐Lindau tumor suppressor protein
Kaelin, W. G. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05781.x · Cited by 12
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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