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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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Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity
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“In addition, mutations in SETD2 are associated with progression of several cancers, such as acute lymphoblastic leukemia and clear cell renal cell carcinoma (ccRCC) (Dalgliesh et al., 2010; Zhang et al., 2012; Zhu et al., 2014).”
BackgroundMutation and Loss of Expression of ARID1A in Uterine Low-grade Endometrioid Carcinoma
Guan, B., Mao, T., Panuganti, P. K., Kuhn, E., Kurman, R. J., Maeda, D., Chen, E., Jeng, Y., Wang, T., & Shih, I. (2011) · The American Journal of Surgical Pathology · doi:10.1097/pas.0b013e318212782a · Cited by 286
“These genes include JARID1C in renal cell carcinoma (1), BRG1 (SMARCA4) in lung carcinoma (12,16) and, most recently, ARID1A in ovarian clear cell and ovarian low-grade endometrioid carcinoma (6,21).”
BackgroundSomatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types
Jones, S., Li, M., Parsons, D. W., Zhang, X., Wesseling, J., Kristel, P., Schmidt, M. K., Markowitz, S. D., Yan, H., Bigner, D. D., et al. (2011) · Human Mutation · doi:10.1002/humu.21633 · Cited by 286
Tumours associated with BAP1 mutations
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“As such, our discovery that kidney-specific Nf2 deletion yields renal carcinomas in the mouse has been complemented recently by the discovery ofNF2mutations in a subset of sporadic human renal tumors (Forbes et al. 2008; Morris and McClatchey 2009; Dalgliesh et al. 2010).”
BackgroundChoosing the right cell line for renal cell cancer research
Brodaczewska, K. K., Szczylik, C. A., Fiedorowicz, M., Porta, C., & Czarnecka, A. M. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0565-8 · Cited by 279
“This cell line was also shown to contain an NF2 mutation, together with SN12C, while Caki-1, A-704, 769-”
BackgroundSETD2 is required for DNA double-strand break repair and activation of the p53-mediated checkpoint
Carvalho, S., Vítor, A. C., Sridhara, S. R. C., Martins, F. B., Raposo, A. C., Desterro, J. M. P., Ferreira, J. A., & de Almeida, S. F. (2014) · eLife · doi:10.7554/elife.02482 · Cited by 282
Cancer Epigenetics: An Introduction
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“In particular, a recent systematic analysis has indicated thatNF2 mutations define a subtype of non-VHL mutated clear cell renal carcinomas (ccRCCs) and targeted deletion of Nf2 in mouse renal epithelia leads to invasive carcinoma by 6–10 months of age (Dalgliesh et al., 2010; Morris and McClatchey, 2009).”
Yamamoto, S., Tsuda, H., Takano, M., Tamai, S., & Matsubara, O. (2011) · Modern Pathology · doi:10.1038/modpathol.2011.189 · Cited by 261
“These genes include the JARID1C gene in renal cell carcinomas”
BackgroundHistone methylation and the DNA damage response
Gong, F., & Miller, K. M. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.09.003 · Cited by 265
Identification of functional cooperative mutations of SETD2 in human acute leukemia
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Self-citationReliable detection of subclonal single-nucleotide variants in tumour cell populations
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“Mutations in genes encoding epigenetic modification enzymes (such as PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2) have been shown to play vital roles in the initiation and development of RCC [21-23].”
BackgroundStructural basis for activity regulation of MLL family methyltransferases
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“Detailed expression and mechanistic analysis will be required to determine the important functional consequences of mutations of the histone modifying genes in clear cell kidney cancer, as reported by Dalgliesh et al. (2010) and Varela et al. (2011).”
BackgroundResultBerghe, W. V. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.03.007 · Cited by 245
“n addition, genetic mutations of epigenetic modifying enzymes dd another level of regulatory complexity [15,64–68].”
BackgroundImpaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas
Papillon‐Cavanagh, S., Lü, C., Gayden, T., Mikael, L. G., Béchet, D., Karamboulas, C., Ailles, L., Karamchandani, J., Marchione, D. M., Garcia, B. A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3757 · Cited by 248
Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing
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“We found that alternative splice forms for some important genes related to tumorigenesis, including SMARC1, KDM6A, and NOTCH1, are highly immunogenic and can contain 40 or more unique neoantigens (Figure 6A) (Dalgliesh et al., 2010; Papadakis et al., 2015).”
Popovic, R., Martínez-García, E., Γιαννοπούλου, Ε., Zhang, Q., Zhang, Q., Ezponda, T., Shah, M. Y., Zheng, Y., Will, C., Small, E. C., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004566 · Cited by 250
“The sequencing of the coding regions and genomes of a variety of human tumors showed that mutations in the epigenetic apparatus are among the most common class of alterations in cancer [47,49,64], further stimulating interest in epigenetically targeted therapies [1].”
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“Dalgliesh et al. performed selected exon sequencing of candidate cancer genes on 101 ccRCCs and discovered several novel recurrent mutations in chromatin remodeling genes including SETD2 and KDM5C [2].”
2-Oxoglutarate-dependent dioxygenases in cancer
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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER
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The Protein Interaction Landscape of the Human CMGC Kinase Group
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“CLK2, for example, forms interactions with three CAPs, including SETD2, a histone lysine N-methyltransferase that was recently linked to renal carcinoma (Dalgliesh et al., 2010).”
BackgroundSignaling pathways in renal cell carcinoma
Gowrishankar, B., & Cairns, P. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.10.7.13247 · Cited by 221
A Clearer View of the Molecular Complexity of Clear Cell Renal Cell Carcinoma
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Oncometabolites in renal cancer
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Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer
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“Mutations in epigenetic regulators make these genes attractive candidates as mediators of epigenetic remodeling in ccRCC 30,37 .”
Epigenetics in cancer therapy and nanomedicine
Roberti, A., Valdes, A. F., Torrecillas, R., Fraga, M. F., & Fernández, A. F. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0675-4 · Cited by 216
Microsatellite instability: an update
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“Notably, all SETD2-deficient clear cell renal cell carcinomas showed frequent small insertion–deletion (indel) mutations and dominant single-nucleotide substitutions (Dalgliesh et al. 2010; Gerlinger et al. 2012), which are hallmarks of MMR deficiency.”
The von Hippel-Lindau Tumor Suppressor Gene
Elias, R. M., Zhang, Q. H., & Brugarolas, J. (2020) · The Cancer Journal · doi:10.1097/ppo.0000000000000480 · Cited by 210
“Targeted sequencing of a ~3500-gene panel revealed recurring truncating SETD2 mutations.(40) Subsequent studies found that nonsilent SETD2 mutations occur in ~20% of ccRCCs.”
BackgroundThe Genetic Basis of Hepatosplenic T-cell Lymphoma
McKinney, M. S., Moffitt, A. B., Gaulard, P., Travert, M., de Leval, L., Nicolae, A., Raffeld, M. A., Jaffe, E. S., Pittaluga, S., Xi, L., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0330 · Cited by 205
“SETD2 has been described as a tumor suppressor gene in other malignancies including clear cell renal carcinoma (42), DLBCL (23), and in a subset of acute leukemias (43).”
BackgroundX-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner
Welstead, G. G., Creyghton, M. P., Bilodeau, S., Cheng, A. W., Markoulaki, S., Young, R. A., & Jaenisch, R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1210787109 · Cited by 194
Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencingPreprint
Pflueger, D., Terry, S., Sboner, A., Habegger, L., Esgueva, R., Lin, P.-C., Svensson, M. A., Kitabayashi, N., Moss, B. J., MacDonald, T. Y., et al. (2010) · Genome Research · doi:10.1101/gr.110684.110 · Cited by 197
“Recent genome-wide sequencing projects have shed light on the landscape of somatic alterations in several cancer genomes including kidney, breast, and colorectal cancer (Sjoblom et al. 2006; Stephens et al. 2009; Dalgliesh et al. 2010).”
BackgroundMar, B. G., Bullinger, L., McLean, K. M., Grauman, P. V., Harris, M. H., Stevenson, K. E., Neuberg, D. S., Sinha, A. U., Sallan, S. E., Silverman, L. B., et al. (2014) · Nature Communications · doi:10.1038/ncomms4469 · Cited by 198
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“For renal cell carcinoma (RCC), large-scale sequencing projects have revealed that, with the exception of VHL TSG, candidate TSGs are mutated in o10% of tumours (Dalgliesh et al., 2010), whereas a much larger number of TSGs are frequently silenced by cancer-specific promoter methylation.”
BackgroundResultInfluentialVariation in genomic landscape of clear cell renal cell carcinoma across Europe
Scélo, G., Riazalhosseini, Y., Greger, L., Létourneau, L., Gonzàlez-Porta, M., Wozniak, M. B., Bourgey, M., Harnden, P., Egevad, L., Jackson, S., et al. (2014) · Nature Communications · doi:10.1038/ncomms6135 · Cited by 195
Targeting Histone Demethylases: A New Avenue for the Fight against Cancer
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Molecular insights into NF2/Merlin tumor suppressor function
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“For clear cell renal cell carcinoma (ccRCC), three of the five commonly mutated genes encode the chromatin regulators PBRM1, SETD2, and BAP1.”
BackgroundInfluentialThe emerging role of fumarate as an oncometabolite
Yang, M., Soga, T., Pollard, P. J., & Adam, J. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00085 · Cited by 189
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Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex
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“%) in MMR (Mismatch repair)-deficient colorectal cancers (Park et al., 2002), and KDM5C mutations are found in ~5% renal cell carcinoma (Dalgliesh et al., 2010; Niu et al., 2012), supporting their proposed tumor suppressor roles.”
Combining molecular and imaging metrics in cancer: radiogenomics
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mTOR pathway in colorectal cancer: an update
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“Although mTOR is frequently activated in human cancers, mutation of the mTOR gene has been found only occasionally [9-11].”
BackgroundKanu, N., Gronroos, E. C., Martinez, P., Burrell, R. A., Goh, X. Y., Bártková, J., Maya‐Mendoza, A., Mistrík, M., Rowan, A., Patel, H., et al. (2015) · Oncogene · doi:10.1038/onc.2015.24 · Cited by 189
“…RCC (ccRCC) is the most common histological subtype, accounting for 80-90% of RCCs. Exome sequencing studies of ccRCC have defined the mutational landscapes of these tumours, revealing that histone modifying enzymes and chromatin remodelling complexes are subject to recurrent mutations (2, 3).”
Self-citationChen, Y., Xu, J., Skanderup, A. J., Dong, Y., Brannon, A. R., Wang, L., Won, H. H., Wang, P. I., Nanjangud, G. J., Jungbluth, A. A., et al. (2016) · Nature Communications · doi:10.1038/ncomms13131 · Cited by 184
“Similar to what have been described in ccRCC and pRCC 10,11,20,15–17 , mutations in chromatin modulation genes are relatively frequent in uRCC, although none of which (for example, SETD2 and BAP1 ) was found to be significantly associated with clinical outcomes in this cohort.”
Renal cell carcinoma: Review of etiology, pathophysiology and risk factors
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SMYD3 Promotes Cancer Invasion by Epigenetic Upregulation of the Metalloproteinase MMP-9
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“Several KDMs have been implicated in development, differentiation or stem cell renewal, and their mutation or deregulation have been linked to cancer and other diseases (2-7).”
BackgroundCarvalho, S., Raposo, A. C., Martins, F. B., Grosso, A. R., Sridhara, S. R. C., Rino, J., Carmo‐Fonseca, M., & de Almeida, S. F. (2013) · Nucleic Acids Research · doi:10.1093/nar/gks1472 · Cited by 180
Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2
Moffitt, A. B., Ondrejka, S. L., McKinney, M. S., Rempel, R. E., Goodlad, J. R., Teh, C. H., Leppä, S., Mannisto, S., Kovanen, P. E., Tse, E., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160894 · Cited by 176
“SETD2 loss in mice is associated with an expansion of γδ T cells, suggesting a novel role for SETD2 in T cell development, in addition to its other described roles in oncogenesis (Dalgliesh et al., 2010; Zhu et al., 2014).”
BackgroundInfluentialModeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade
Gu, Y., Cohn, S., Christie, A. L., McKenzie, T., Wolff, N. C., Do, Q. N., Madhuranthakam, A. J., Pedrosa, I., Wang, T., Dey, A., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0292 · Cited by 187
Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer
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“In addition, mutations in NF2 have been commonly documented in glioblastoma [96], mesothelioma [97], renal [98] and breast cancer [99] suggesting that in humans, the cells of the liver that lead to HCC or CC may not be susceptible to NF2 mutation or loss.”
Lee, S., Park, H. Y., Kang, S. Y., Kim, S. J., Hwang, J., Lee, S., Kwak, S. H., Park, K. S., Yoo, H. Y., Kim, W. S., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3776 · Cited by 176
“8% of renal cell carcinoma [28] and 66.”
BackgroundLoss of PBRM1 expression is associated with renal cell carcinoma progression
Pawłowski, R., Mühl, S. M., Sulser, T., Krek, W., Moch, H., & Schraml, P. (2012) · International Journal of Cancer · doi:10.1002/ijc.27822 · Cited by 170
Genomic profiling in renal cell carcinoma
Dizman, N., Philip, E. J., & Pal, S. K. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-0301-x · Cited by 171
Epigenetic aberrations during oncogenesis
Hatziapostolou, M., & Iliopoulos, D. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0624-z · Cited by 173
“H3K4me Renal cell carcinoma MLL2 [76]”
Epigenetic Regulation by Lysine Demethylase 5 (KDM5) Enzymes in Cancer
Blair, L. P., Cao, J. P., Zou, M. R., Sayegh, J., & Yan, Q. (2011) · Cancers · doi:10.3390/cancers3011383 · Cited by 172
“Finally, genomic alterations (amplification or deletion) and/or point mutations of several histone methyltransferses and demethylases are increasingly being identified in cancers through the use of high-density SNP arrays and deep sequencing technologies [8,10-13,69,70].”
BackgroundInfluentialA histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice
Pai, C., Deegan, R. S., Subramanian, L., Gal, C., Sarkar, S., Blaikley, E., Walker, C. A., Hulme, L., Bernhard, E. J., Codlin, S., et al. (2014) · Nature Communications · doi:10.1038/ncomms5091 · Cited by 176
Chronotherapy and the molecular clock: Clinical implications in oncology☆
Innominato, P. F., Lévi, F., & Bjarnason, G. A. (2010) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2010.06.002 · Cited by 168
Wang, L., & Shilatifard, A. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.01.001 · Cited by 165
“KDM6A is also frequently mutated in human clear cell renal cell carcinoma (ccRCC) (Dalgliesh et al., 2010), which is the most common form of adult kidney cancer (Rini et al.”
BackgroundThe VHL-dependent regulation of microRNAs in renal cancer
Neal, C. S., Michael, M., Rawlings, L. H., der Hoek, M. B. V., & Gleadle, J. (2010) · BMC Medicine · doi:10.1186/1741-7015-8-64 · Cited by 164
“These mechanisms potentially include disruptions in SETD2 (histone H3K36 methyltransferase) or JARID1C (histone H3K4 demethylase), which have both been recently identified as having truncating mutations in approximately 3% of cc RCC tumours [54].”
BackgroundLin, W., Cao, J. P., Liu, J., Beshiri, M. L., Fujiwara, Y., Francis, J. M., Cherniack, A. D., Geisen, C., Blair, L. P., Zou, M. R., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1110104108 · Cited by 166
“Finally, copy number changes and intragenic mutations affecting histone methyltransferses and demethylases, such as the UTX H3K27 histone demethylase, are increasingly being identified in cancers (5, 55, 56).”
Joseph, R. W., Kapur, P., Serie, D., Eckel‐Passow, J. E., Parasramka, M. A., Ho, T. H., Cheville, J. C., Frenkel, E. P., Rakheja, D., Brugarolas, J., et al. (2013) · Cancer · doi:10.1002/cncr.28521 · Cited by 165
The cancer COMPASS: navigating the functions of MLL complexes in cancer
Ford, D. J., & Dingwall, A. K. (2015) · Cancer Genetics · doi:10.1016/j.cancergen.2015.01.005 · Cited by 169
State of the Science: An Update on Renal Cell Carcinoma
Jonasch, E. W., Futreal, P. A., Davis, I. J., Bailey, S. T., Kim, W. Y., Brugarolas, J., Giaccia, A. J., Kurban, G., Pause, A., Frydman, J., et al. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0117 · Cited by 165
“Less common mutations were also identified in two methyltransferases, SETD2 and MLL2, and two demethylases, UTX (KDM6A) and JARID1C (KDM5C) [18] (Figure 1).”
BackgroundInfluentialSelf-citationNPHP4, a cilia-associated protein, negatively regulates the Hippo pathway
Habbig, S., Bartram, M. P., Müller, R., Schwarz, R., Andriopoulos, N., Chen, S., Sägmüller, J. G., Hoehne, M., Burst, V. R., Liebau, M. C., et al. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201009069 · Cited by 173
“, 1994) and in renal cell carcinoma (Forbes et al., 2008; Morris and McClatchey, 2009; Dalgliesh et al., 2010), the Ser/Thr kinases MST1/2 (mammalian STE20 kinases 1 and 2) and Lats1/2 (large tumor suppressor 1 and 2), together with their coactivators WW45 and Mob.”
BackgroundSETD2: an epigenetic modifier with tumor suppressor functionality
Li, J., Duns, G., Westers, H., Sijmons, R. H., van den Berg, A., & Kok, K. (2016) · Oncotarget · doi:10.18632/oncotarget.9368 · Cited by 163
“The first report on SETD2 mutations in cancer dates from 2010 when Dalgliesh et al identified inactivation mutations in ccRCC [90].”
BackgroundGozdecka, M., Meduri, E., Mazan, M. M., Tzelepis, K., Dudek, M., Knights, A. J., Pardo, M., Yu, L., Choudhary, J. S., Metzakopian, E., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0114-z · Cited by 160
Genetic and metabolic hallmarks of clear cell renal cell carcinoma
Sanchez, D. J., & Simon, M. C. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.06.003 · Cited by 164
“Inactivating or truncating mutations in JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase, and UTX (KMD6A) a histone H3 lysine 27 demethylase were identified in another study as positively selected for in ccRCC compared to other cancers [40], [41].”
BackgroundKaelin, W. G. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010975 · Cited by 161
“Intragenic HIF1a mutations have been identified in kidney cancer genome sequencing projects and, when tested, have proven to be loss of func- tion (Morris et al. 2009; Dalgliesh et al. 2010; Shen et al. 2011).”
InfluentialSQSTM1 Is a Pathogenic Target of 5q Copy Number Gains in Kidney Cancer
Li, L., Shen, C., Nakamura, E., Ando, K., Signoretti, S., Beroukhim, R., Cowley, G. S., Lizotte, P. H., Liberzon, E., Bair, S. M., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.10.025 · Cited by 166
“…also harbors the renal cancer suppressors PBRM1, BAP1, and SETD2, is found in virtually all ccRCCs (Cancer Genome Atlas Research Network, 2013; Dalgliesh et al., 2010; Guo et al., Significance Kidney cancer is one of the ten most common cancers in the gene on chromosome 3p is the signature…”
Epigenetics in renal cell cancer: mechanisms and clinical applications
Joosten, S. C., Smits, K. M., Aarts, M. J. B., Melotte, V., Koch, A., Tjan‐Heijnen, V. C. G., & van Engeland, M. (2018) · Nature Reviews Urology · doi:10.1038/s41585-018-0023-z · Cited by 166
Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
Yuan, H., Li, N., Fu, D., Ren, J., Hui, J., Peng, J., Liu, Y., Qiu, T., Jiang, M., Pan‐Hammarström, Q., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci94292 · Cited by 165
Schödel, J., Bardella, C., Sciesielski, L. K., Brown, J. M., Pugh, C. W., Buckle, V. J., Tomlinson, I. P. M., Ratcliffe, P. J., & Mole, D. R. (2012) · Nature Genetics · doi:10.1038/ng.2204 · Cited by 163
MLL3/MLL4/COMPASS Family on Epigenetic Regulation of Enhancer Function and Cancer
Sze, C. C., & Shilatifard, A. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026427 · Cited by 164
“This functional distinction of UTX between molecular subtypes of T-ALL was further supported in patientderived xenografts, in which treatment with H3K27 demethylase inhibitor GSK-J4 dramatically reduced percentage of human leukemic blasts and splenomegaly in TAL1-positive models, with no effect on TAL1-negative models…”
BackgroundInfluentialWozniak, M. B., Calvez‐Kelm, F. L., Abedi‐Ardekani, B., Byrnes, G. B., Durand, G., Carreira, C., Michelon, J., Janout, V., Holcátová, I., Foretová, L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057886 · Cited by 156
“Several microarray studies have been performed to detect gene expression signatures in renal cancer that would provide diagnostic and prognostic information [6,17,18,31,32,33,34,35,36,37,38].”
BackgroundInfluentialSinefungin Derivatives as Inhibitors and Structure Probes of Protein Lysine Methyltransferase SETD2
Zheng, W., Ibáñez, G., Wu, H., Blum, G., Zeng, H., Dong, A., Li, F., Hajian, T., Allali‐Hassani, A., Amaya, M. F., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja307060p · Cited by 156
Niu, X., Zhang, T., Liao, L., Zhou, L., Lindner, D. J., Zhou, M., Rini, B. I., Yan, Q., & Yang, H. (2011) · Oncogene · doi:10.1038/onc.2011.266 · Cited by 155
“of the tumor suppressor von Hippel–Lindau (VHL) occurs in the majority of the tumors and is causal for the pathogenesis of ccRCC. Recently, a large-scale genomic sequencing study of ccRCC tumors revealed that enzymes that regulate histone H3 lysine 4 trimethylation (H3K4Me3), such as JARID1C/KDM5C/SMCX and MLL2, were…”
BackgroundInfluentialThe Roles of 2-Hydroxyglutarate
Du, X., & Hu, H. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.651317 · Cited by 160
“When IDH is mutant, α-KG is consumed to generate a concentration as high as 3–35 mM of D-2HG (Dang et al., 2010), which far exceeds the IC50 of these α-KG-dependent dioxygenases; this provides clues to detect the mechanism of the tumorigenic effect of D-2HG, and similarly of L-2HG.”
BackgroundInfluentialDevelopment of Chemotherapy with Cell-Cycle Inhibitors for Adult and Pediatric Cancer Therapy
Mills, C. C., Kolb, E. A., & Sampson, V. B. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2782 · Cited by 160
“This agent demonstrates single-agent activity in sarcoma cell lines (39) and is sensitive to SETD2 mutations (the sole methyltransferase for H3K36me3) in kidney cancer (40, 41).”
Understanding histone H3 lysine 36 methylation and its deregulation in disease
Li, J., Ahn, J. H., & Wang, G. G. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03144-y · Cited by 155
Grosso, A. R., Leite, A. P., Carvalho, S., Matos, M. R., Martins, F. B., Vítor, A. C., Desterro, J. M., Carmo-Fonseca, M., & de Almeida, S. F. (2015) · eLife · doi:10.7554/elife.09214 · Cited by 152
Myeloid malignancies: mutations, models and management
Murati, A., Brecqueville, M., Devillier, R., Mozziconacci, J., Gelsi‐Boyer, V., & Birnbaum, D. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-304 · Cited by 163
“The latter phenomenon has been observed in genomewide analyses of many neoplasias [28,66,67].”
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Mo, W., Chen, J., Patel, A. J., Zhang, L., Chau, V., Li, Y., Cho, W., Lim, K., Xu, J., Lazar, A. J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.01.053 · Cited by 150
The H3K27me3 demethylase UTX in normal development and disease
der Meulen, J. V., Speleman, F., & Vlierberghe, P. V. (2014) · Epigenetics · doi:10.4161/epi.28298 · Cited by 150
A687V EZH2 is a gain‐of‐function mutation found in lymphoma patients
Majer, C. R., Jin, L., Scott, M. P., Knutson, S. K., Kuntz, K. W., Keilhack, H., Smith, J. J., Moyer, M. P., Richon, V. M., Copeland, R. A., et al. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.07.066 · Cited by 154
Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis
Wang, S., Gu, Y., Wolff, N. C., Stefanius, K., Christie, A. L., Dey, A., Hammer, R. E., Xie, X.-J., Rakheja, D., Pedrosa, I., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414789111 · Cited by 152
Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice
Albers, J., Rajski, M., Schönenberger, D., Harlander, S., Schraml, P., von Teichman, A., Georgiev, S., Wild, P. J., Moch, H., Krek, W., et al. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201202231 · Cited by 149
“Similarly, SETD2 is mutated in a small fraction of ccRCCs (Dalgliesh et al, 2010) and has been suggested to regulate a subset of p53 target genes (Xie et al, 2008).”
LINE-1 expression and retrotransposition in Barrett’s esophagus and esophageal carcinoma
Doucet-O’Hare, T. T., Rodić, N., Sharma, R., Darbari, I., Abril, G., Choi, J. A., Ahn, J. Y., Cheng, Y., Anders, R. A., Burns, K. H., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1502474112 · Cited by 158
Lysine Demethylases Inhibitors
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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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