IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Open accessAbstract
Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.
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IDH mutant gliomas show a CpG island methylator phenotype.
“IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, though the functional significance of this altered epigenetic state remains unclear.”
From Insulator dysfunction and oncogene activation in IDH mutant gliomas (2016) · cites this paper as [11]
D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA.
“As a result, D-2HG accumulation in cancer cells expressing mutant IDH results in hypermethylation of histones and CpG islands in DNA (Figueroa et al., 2010; Lu et al., 2012; Turcan et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Turcan et al., 2012
Interference with TET family proteins causes the CpG island methylator phenotype.
“Specifically, owing to the interference with TET family proteins, the mutation causes the CpG island methylator phenotype116,123.”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [123]
IDH-driven gliomas, leukemias, and chondrosarcomas display prominent CpG island hypermethylation reminiscent of SDH- and FH-deficient cancers.
“Indeed, IDH-driven gliomas, leukemias and chondrosarcomas display a prominent CpG island hypermethylation, reminiscent of the hypermethylator phenotype seen in SDH- and FH-deficient cancers (Figueroa et al., 2010; Lu et al., 2013; Turcan et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Turcan et al., 2012
In the cancer setting, 2-HG influences a number of biological processes, including cell differentiation, DNA methylation, and histone methylation.
“In the cancer setting, 2-HG has been shown to influence a number of biological processes, including cell differentiation, DNA methylation, and histone methylation (79–82), leading to its classification as an oncometabolite.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [82]
CD8+ T cells are highly dependent on activation of HIF-1α and glycolysis, which mediates trafficking into hypoxic tumour environments and inflamed tissue.
“Like TH17 cells, CD8+ T cells are highly dependent on the activation of HIF-1α and glycolysis, which is responsible for mediating trafficking into hypoxic tumour environments and inflamed tissue147,148.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [147]
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Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
The Cancer Genome Atlas Research Network (2008) · Nature · doi:10.1038/nature07385 · Cited by 7,735 · see citing works
Verhaak, R. G. W., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., Wilkerson, M. D., Miller, C. R., Ding, L., Golub, T., Mesirov, J. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.020 · Cited by 7,575 · see citing works
<i>MGMT</i> Gene Silencing and Benefit from Temozolomide in Glioblastoma
Hegi, M. E., Diserens, A.-C., Gorlia, T., Hamou, M.-F., de Tribolet, N., Weller, M., Kros, J. M., Hainfellner, J. A., Mason, W., Mariani, L., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043331 · Cited by 7,405 · see citing works
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857 · see citing works
<i>IDH1</i> and <i>IDH2</i> Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847 · see citing works
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515 · see citing works
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154 · see citing works
Self-citationConsed: a graphical tool for sequence finishing.Preprint
Gordon, D., Abajian, C., & Green, P. (1998) · Genome Research · doi:10.1101/gr.8.3.195 · Cited by 3,706 · see citing works
CNS stem cells express a new class of intermediate filament protein
Lendahl, U., Zimmerman, L. B., & McKay, R. D. G. (1990) · Cell · doi:10.1016/0092-8674(90)90662-x · Cited by 3,164 · see citing works
The Consensus Coding Sequences of Human Breast and Colorectal Cancers
Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D. L., Leary, R. J., Ptak, J., Silliman, N., et al. (2006) · Science · doi:10.1126/science.1133427 · Cited by 3,161 · see citing works
PANTHER: A Library of Protein Families and Subfamilies Indexed by FunctionPreprint
Thomas, P. D., Campbell, M. J., Kejariwal, A., Mi, H., Karlak, B., Daverman, R., Diemer, K., Muruganujan, A., & Narechania, A. (2003) · Genome Research · doi:10.1101/gr.772403 · Cited by 2,912 · see citing works
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA
He, Y., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., et al. (2011) · Science · doi:10.1126/science.1210944 · Cited by 2,776 · see citing works
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766 · see citing works
Self-citationIsolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma
Galli, R., Binda, E., Orfanelli, U., Cipelletti, B., Gritti, A., Vitis, S. D., Fiocco, R., Foroni, C., DiMeco, F., & Vescovi, A. L. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1364 · Cited by 2,570 · see citing works
CpG island methylator phenotype in colorectal cancer
Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J. G., Baylin, S. B., & Issa, J. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.15.8681 · Cited by 2,506 · see citing works
Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.017 · Cited by 2,337 · see citing works
Malignant astrocytic glioma: genetics, biology, and paths to treatment
Furnari, F. B., Fenton, T., Bachoo, R. M., Mukasa, A., Stommel, J. M., Stegh, A., Hahn, W. C., Ligon, K. L., Louis, D. N., Brennan, C., et al. (2007) · Genes & Development · doi:10.1101/gad.1596707 · Cited by 2,316 · see citing works
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219 · see citing works
Reich, M. M., Liefeld, T., Gould, J., Lerner, J., Tamayo, P., & Mesirov, J. P. (2006) · Nature Genetics · doi:10.1038/ng0506-500 · Cited by 2,035 · see citing works
Ward, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020 · cited 1× · see citing works
“Mutation of IDH imparts the ability to produce 2-hydroxyglutarate (2-HG), a potential oncometabolit”
BackgroundSelf-citationHigh density DNA methylation array with single CpG site resolution
Bibikova, M., Barnes, B., Tsan, C., Ho, V., Klotzle, B., Le, J. M., Delano, D., Zhang, L., Schroth, G. P., Gunderson, K. L., et al. (2011) · Genomics · doi:10.1016/j.ygeno.2011.07.007 · Cited by 1,727 · see citing works
Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitionsPreprint
Bracken, A. P., Dietrich, N., Pasini, D., Hansen, K. H., & Helin, K. (2006) · Genes & Development · doi:10.1101/gad.381706 · Cited by 1,258 · see citing works
Ohm, J. E., McGarvey, K. M., Yu, X., Cheng, L., Schuebel, K. E., Cope, L., Mohammad, H. P., Chen, W., Daniel, V. C., Yu, W., et al. (2007) · Nature Genetics · doi:10.1038/ng1972 · Cited by 1,130 · see citing works
Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome
Sandoval, J., Heyn, H., Moran, S., Serra-Musach, J., Pujana, M. A., Bibikova, M., & Esteller, M. (2011) · Epigenetics · doi:10.4161/epi.6.6.16196 · Cited by 990 · see citing works
Nickerson, D. A. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.14.2745 · Cited by 931 · see citing works
Silencing of transgene transcription precedes methylation of promoter DNA and histone H3 lysine 9
Mutskov, V. J., & Felsenfeld, G. (2003) · The EMBO Journal · doi:10.1038/sj.emboj.7600013 · Cited by 297 · see citing works
Sonoda, Y., Ozawa, T., Hirose, Y., Aldape, K. D., McMahon, M., Berger, M. S., & Pieper, R. O. (2001) · PubMed · Cited by 278 · see citing works
Breast Cancer Methylomes Establish an Epigenomic Foundation for Metastasis
Fang, F., Turcan, Ş., Rimner, A., Kaufman, A., Giri, D. D., Morris, L. G. T., Shen, R., Seshan, V., Mo, Q., Heguy, A., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001875 · Cited by 267 · see citing works
Self-citationIdentification of the JNK Signaling Pathway as a Functional Target of the Tumor Suppressor PTEN
Vivanco, I., Palaskas, N. J., Tran, C., Finn, S. P., Getz, G. A., Kennedy, N. J., Jiao, J., Rose, J. A., Xie, W., Loda, M. F., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.04.021 · Cited by 245 · see citing works
Self-citationSonoda, Y., Ozawa, T., Aldape, K. D., Deen, D. F., Berger, M. S., & Pieper, R. O. (2001) · PubMed · Cited by 224 · see citing works
DNA methylation in glioblastoma: impact on gene expression and clinical outcome
Etcheverry, A., Aubry, M., de Tayrac, M., Vauléon, É., Boniface, R., Guénot, F., Saïkali, S., Hamlat, A., Riffaud, L., Meneï, P., et al. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-701 · Cited by 221 · see citing works
Vlassenbroeck, I., Califice, S., Diserens, A., Migliavacca, E., Straub, J., Stefano, I. D., Moreau, F., Hamou, M., Renard, I., Delorenzi, M., et al. (2008) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2008.070169 · Cited by 198 · see citing works
Molecular Concepts Analysis Links Tumors, Pathways, Mechanisms, and Drugs
Rhodes, D. R., Sundaram, S. K., Tomlins, S. A., Mahavisno, V., Kasper, N. M., Varambally, R., Barrette, T. R., Ghosh, D., Varambally, S., & Chinnaiyan, A. M. (2007) · Neoplasia · doi:10.1593/neo.07292 · Cited by 142 · see citing works
Cheng, Y., Pinças, H., Bacolod, M. D., Schemmann, G. S., Giardina, S. F., Huang, J., Barral, S., Idrees, K., Khan, S. A., Zeng, Z., et al. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0216 · Cited by 108 · see citing works
Filippis, L. D., Lamorte, G., Snyder, E. Y., Malgaroli, A., & Vescovi, A. L. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0040 · Cited by 88 · see citing works
PolyScan: An automatic indel and SNP detection approach to the analysis of human resequencing dataPreprint
Chen, K., McLellan, M. D., Ding, L., Wendl, M. C., Kasai, Y., Wilson, R. K., & Mardis, E. R. (2007) · Genome Research · doi:10.1101/gr.6151507 · Cited by 79 · see citing works
Docherty, S. J., Davis, O. S. P., Haworth, C. M. A., Plomin, R. J., & Mill, J. S. (2009) · Epigenetics & Chromatin · doi:10.1186/1756-8935-2-3 · Cited by 55 · see citing works
Identification of p18INK4c as a Tumor Suppressor Gene in Glioblastoma Multiforme
Solomon, D. A., Kim, J.-S., Jenkins, S. A., Ressom, H. W., Huang, M. C., Coppa, N. D., Mabanta, L., Bigner, D. D., Yan, H., Jean, W. C., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6388 · Cited by 55 · see citing works
Genomic mutation consequence calculator
Major, J. E. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm339 · Cited by 18 · see citing works
Defined human cellular systems in the study of glioma development
Pieper, R. O. (2003) · Frontiers in bioscience · doi:10.2741/983 · Cited by 11 · see citing works
Flagged first, then by citations
2 of the 44 references couldn’t be matched to a known paper.
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Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863 · see citing works
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
Self-citationMitochondria: In Sickness and in Health
Nunnari, J., & Suomalainen, A. (2012) · Cell · doi:10.1016/j.cell.2012.02.035 · Cited by 3,479 · see citing works
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
Self-citationFundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013 · see citing works
Metabolic reprogramming and cancer progression
Faubert, B., Solmonson, A., & DeBerardinis, R. J. (2020) · Science · doi:10.1126/science.aaw5473 · Cited by 2,740 · see citing works
Wallace, D. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3365 · Cited by 2,404 · see citing works
Ceccarelli, M., Barthel, F. P., Malta, T. M., Sabedot, T. S., Salama, S. R., Murray, B. A., Morozova, O., Newton, Y., Radenbaugh, A., Pagnotta, S. M., et al. (2016) · Cell · doi:10.1016/j.cell.2015.12.028 · Cited by 2,200 · see citing works
Self-citationThe diverse roles of DNA methylation in mammalian development and disease
Greenberg, M., & Bourc’his, D. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0159-6 · Cited by 2,160 · see citing works
Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation
Malta, T. M., Sokolov, A., Gentles, A. J., Burzykowski, T., Poisson, L., Weinstein, J. N., Kamińska, B., Huelsken, J., Omberg, L., Gevaert, O., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.034 · Cited by 2,180 · see citing works
Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D.-A., Jones, D. T. W., Konermann, C., Pfaff, E., Tönjes, M., Sill, M., Bender, S., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.024 · Cited by 1,828 · see citing works
Teschendorff, A. E., Marabita, F., Lechner, M., Bartlett, T. E., Tegner, J. N., Gómez-Cabrero, D., & Beck, S. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts680 · Cited by 1,652 · see citing works
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers
Sondka, Z., Bamford, S., Cole, C. G., Ward, S. A., Dunham, I., & Forbes, S. A. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0060-1 · Cited by 1,597 · see citing works
Bañales, J. M., Cardinale, V., Carpino, G., Marzioni, M., Andersen, J. B., Invernizzi, P., Lind, G. E., Folseraas, T., Forbes, S. J., Fouassier, L., et al. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.51 · Cited by 1,382 · see citing works
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
Epigenetic Determinants of CancerPreprint
Baylin, S. B., & Jones, P. A. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019505 · Cited by 1,363 · see citing works
Lessons from the Cancer Genome
Garraway, L. A., & Lander, E. S. (2013) · Cell · doi:10.1016/j.cell.2013.03.002 · Cited by 1,322 · see citing works
Insulator dysfunction and oncogene activation in IDH mutant gliomas
Flavahan, W. A., Drier, Y., Liau, B. B., Gillespie, S. M., Venteicher, A. S., Stemmer-Rachamimov, A. O., Suvà, M. L., & Bernstein, B. E. (2016) · Nature · doi:10.1038/nature16490 · Cited by 1,288 · see citing works
van den Bent, M. J., Brandes, A. A., TAPHOORN, M. J. B., Kros, J. M., Kouwenhoven, M. C. M., Delattre, J., Bernsen, H. J. J. A., Frénay, M., Tijssen, C. C., Grisold, W., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.2229 · Cited by 1,220 · see citing works
Cancer Genetics and Epigenetics: Two Sides of the Same Coin?
You, J. S., & Jones, P. A. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.06.008 · Cited by 1,163 · see citing works
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells
Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., et al. (2013) · Science · doi:10.1126/science.1236062 · Cited by 1,153 · see citing works
Self-citationTargeting the cancer epigenome for therapy
Jones, P. A., Issa, J. J., & Baylin, S. B. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.93 · Cited by 1,132 · see citing works
The Definition of Primary and Secondary Glioblastoma
Ohgaki, H., & Kleihues, P. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3002 · Cited by 1,125 · see citing works
Weller, M., Wick, W., Aldape, K. D., Brada, M., Berger, M. S., Pfister, S. M., Nishikawa, R., Rosenthal, M. A., Wen, P. Y., Stupp, R., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.17 · Cited by 1,129 · see citing works
Mesenchymal Differentiation Mediated by NF-κB Promotes Radiation Resistance in Glioblastoma
Bhat, K., Balasubramaniyan, V., Vaillant, B. D., Ezhilarasan, R., Hummelink, K., Hollingsworth, F., Wani, K., Heathcock, L. E., James, J. D., Goodman, L. D., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.08.001 · Cited by 1,110 · see citing works
Role of TET enzymes in DNA methylation, development, and cancer
Rasmussen, K. D., & Helin, K. (2016) · Genes & Development · doi:10.1101/gad.276568.115 · Cited by 1,040 · see citing works
Donohoe, D. R., Collins, L. B., Wali, A., Bigler, R., Sun, W., & Bultman, S. J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.08.033 · Cited by 993 · see citing works
Navigating the DNA methylation landscape of cancer
Nishiyama, A., & Nakanishi, M. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.05.002 · Cited by 974 · see citing works
Targeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971 · see citing works
Cancer Cell Metabolism: One Hallmark, Many Faces
Cantor, J. R., & Sabatini, D. M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0345 · Cited by 945 · see citing works
How cancer metabolism is tuned for proliferation and vulnerable to disruption
Schulze, A., & Harris, A. L. (2012) · Nature · doi:10.1038/nature11706 · Cited by 927 · see citing works
Influence of Metabolism on Epigenetics and Disease
Kaelin, W. G., & McKnight, S. L. (2013) · Cell · doi:10.1016/j.cell.2013.03.004 · Cited by 920 · see citing works
Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance
Easwaran, H., Tsai, H.-C., & Baylin, S. B. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.015 · Cited by 915 · see citing works
Interplay between the Cancer Genome and Epigenome
Shen, H., & Laird, P. W. (2013) · Cell · doi:10.1016/j.cell.2013.03.008 · Cited by 912 · see citing works
Goodenberger, M. L., & Jenkins, R. B. (2012) · Cancer Genetics · doi:10.1016/j.cancergen.2012.10.009 · Cited by 864 · see citing works
Bender, S., Tang, Y., Lindroth, A. M., Hovestadt, V., Jones, D. T. W., Kool, M., Zapatka, M., Northcott, P. A., Sturm, D., Wang, W., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.10.006 · Cited by 818 · see citing works
Glioma Subclassifications and Their Clinical Significance
Chen, R., Smith-Cohn, M., Cohen, A. L., & Colman, H. (2017) · Neurotherapeutics · doi:10.1007/s13311-017-0519-x · Cited by 812 · see citing works
Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation
Wang, F., Travins, J., DeLaBarre, B., Penard-Lacronique, V., Schalm, S., Hansen, E., Straley, K., Kernytsky, A., Liu, W., Gliser, C., et al. (2013) · Science · doi:10.1126/science.1234769 · Cited by 804 · see citing works
DNA methylation profiling in the clinic: applications and challenges
Heyn, H., & Esteller, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3270 · Cited by 747 · see citing works
Genetic and molecular epidemiology of adult diffuse glioma
Molinaro, A. M., Taylor, J. W., Wiencke, J. K., & Wrensch, M. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0220-2 · Cited by 708 · see citing works
Metabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
A vaccine targeting mutant IDH1 induces antitumour immunity
Schumacher, T., Bunse, L., Pusch, S., Sahm, F., Wiestler, B., Quandt, J., Menn, O., Osswald, M., Oezen, I., Ott, M., et al. (2014) · Nature · doi:10.1038/nature13387 · Cited by 707 · see citing works
Dynamic DNA methylation across diverse human cell lines and tissuesPreprint
Varley, K. E., Gertz, J., Bowling, K. M., Parker, S. L., Reddy, T. E., Pauli, F., Cross, M. K., Williams, B. A., Stamatoyannopoulos, J. A., Crawford, G. E., et al. (2013) · Genome Research · doi:10.1101/gr.147942.112 · Cited by 693 · see citing works
Metabolic Regulation of Epigenetics
Lu, C., & Thompson, C. B. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.001 · Cited by 699 · see citing works
Self-citationIDH mutation in glioma: molecular mechanisms and potential therapeutic targets
Han, S., Liu, Y., Cai, S. J., Qian, M., Ding, J., Larion, M., Gilbert, M. R., & Yang, C. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0814-x · Cited by 661 · see citing works
Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine
Zhang, J., Pavlova, N. N., & Thompson, C. B. (2017) · The EMBO Journal · doi:10.15252/embj.201696151 · Cited by 651 · see citing works
Self-citationTranscription factors as readers and effectors of DNA methylation
Zhu, H., Wang, G., & Qian, J. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.83 · Cited by 649 · see citing works
Principles of DNA methylation and their implications for biology and medicine
Dor, Y., & Cedar, H. (2018) · The Lancet · doi:10.1016/s0140-6736(18)31268-6 · Cited by 640 · see citing works
IDH1 and IDH2 mutations in gliomas
Cohen, A. L., Holmen, S. L., & Colman, H. (2013) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-013-0345-4 · Cited by 629 · see citing works
The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications
Linehan, W. M., & Ricketts, C. J. (2019) · Nature Reviews Urology · doi:10.1038/s41585-019-0211-5 · Cited by 629 · see citing works
Epigenomic alterations define lethal CIMP-positive ependymomas of infancy
Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., Wang, X., Gallo, M., Garzia, L., Zayne, K., et al. (2014) · Nature · doi:10.1038/nature13108 · Cited by 607 · see citing works
CGCG clinical practice guidelines for the management of adult diffuse gliomas
Jiang, T., Mao, Y. Q., Ma, W., Mao, Q., You, Y., Yang, X., Jiang, C., Kang, C., Li, X., Chen, L., et al. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.01.024 · Cited by 605 · see citing works
Frequent ATRX , CIC , FUBP1 and IDH1 mutations refine the classification of malignant gliomas
Jiao, Y., Killela, P. J., Reitman, Z. J., Rasheed, B. A., Heaphy, C. M., de Wilde, R. F., Rodríguez, F. J., Rosemberg, S., Oba‐Shinjo, S. M., Marie, S. K. N., et al. (2012) · Oncotarget · doi:10.18632/oncotarget.588 · Cited by 584 · see citing works
MGMT testing—the challenges for biomarker-based glioma treatment
Wick, W., Weller, M., van den Bent, M. J., Sanson, M., Weiler, M., von Deimling, A., Plass, C., Hegi, M. E., Platten, M., & Reifenberger, G. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.100 · Cited by 580 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
Emerging insights into the molecular and cellular basis of glioblastomaPreprint
Dunn, G. P., Rinne, M. L., Wykosky, J., Genovese, G., Quayle, S. N., Dunn, I. F., Agarwalla, P. K., Chheda, M. G., Campos, B., Wang, A., et al. (2012) · Genes & Development · doi:10.1101/gad.187922.112 · Cited by 559 · see citing works
Sulkowski, P. L., Corso, C. D., Robinson, N. D., Scanlon, S. E., Purshouse, K. R., Bai, H., Liu, Y., Sundaram, R. K., Hegan, D. C., Fons, N. R., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aal2463 · Cited by 556 · see citing works
Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
Sturm, D., Bender, S., Jones, D. T. W., Lichter, P., Grill, J., Becher, O., Hawkins, C., Majewski, J., Jones, C., Costello, J. F., et al. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3655 · Cited by 555 · see citing works
Glioblastoma stem cells: lessons from the tumor hierarchy in a lethal cancerPreprint
Gimple, R. C., Bhargava, S., Dixit, D., & Rich, J. N. (2019) · Genes & Development · doi:10.1101/gad.324301.119 · Cited by 539 · see citing works
Glioma epigenetics: From subclassification to novel treatment options
Gusyatiner, O., & Hegi, M. E. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.11.010 · Cited by 547 · see citing works
Mitochondrial DNA copy number variation across human cancers
Reznik, E., Miller, M. L., Şenbabaoğlu, Y., Riaz, N., Sarungbam, J., Tickoo, S. K., Al‐Ahmadie, H. A., Lee, W., Seshan, V., Hakimi, A. A., et al. (2016) · eLife · doi:10.7554/elife.10769 · Cited by 515 · see citing works
Glioblastoma: From Molecular Pathology to Targeted Treatment
Cloughesy, T. F., Cavenee, W. K., & Mischel, P. S. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130324 · Cited by 513 · see citing works
Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake
Flavahan, W. A., Wu, Q., Hitomi, M., Rahim, N., Kim, Y., Sloan, A. E., Weil, R. J., Nakano, I., Sarkaria, J. N., Stringer, B. W., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3510 · Cited by 504 · see citing works
IDH mutations in cancer and progress toward development of targeted therapeutics
Dang, L., Yen, K., & Attar, E. C. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw013 · Cited by 509 · see citing works
Mitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 502 · see citing works
Chan-on, W., Nairismägi, M., Ong, C. K., Lim, W. K., Dima, S., Pairojkul, C., Lim, K. H., McPherson, J. R., Cutcutache, I., Heng, H. L., et al. (2013) · Nature Genetics · doi:10.1038/ng.2806 · Cited by 495 · see citing works
Baumert, B. G., Hegi, M. E., van den Bent, M. J., von Deimling, A., Gorlia, T., Hoang-Xuan, K., Brandes, A. A., Kantor, G., Taphoorn, M. J. B., Hassel, M. B., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30313-8 · Cited by 495 · see citing works
BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1
Tönjes, M., Barbus, S., Park, Y. J., Wang, W., Schlotter, M., Lindroth, A. M., Pleier, S. V., Bai, A. H. C., Karra, D., Piro, R. M., et al. (2013) · Nature Medicine · doi:10.1038/nm.3217 · Cited by 486 · see citing works
Self-citationWirsching, H., Galanis, E., & Weller, M. (2016) · Handbook of clinical neurology · doi:10.1016/b978-0-12-802997-8.00023-2 · Cited by 487 · see citing works
Yen, K., Travins, J., Wang, F., David, M. D., Artin, E., Straley, K., Padyana, A., Gross, S., DeLaBarre, B., Tobin, E., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1034 · Cited by 471 · see citing works
Diffuse Glioma Heterogeneity and Its Therapeutic Implications
Nicholson, J., & Fine, H. A. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1474 · Cited by 459 · see citing works
IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives
Yang, H., Ye, D., Guan, K., & Xiong, Y. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1773 · Cited by 459 · see citing works
Plass, C., Pfister, S. M., Lindroth, A. M., Bogatyrova, O., Claus, R., & Lichter, P. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3554 · Cited by 448 · see citing works
Oncogenic Isocitrate Dehydrogenase Mutations: Mechanisms, Models, and Clinical Opportunities
Cairns, R. A., & Mak, T. W. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0083 · Cited by 452 · see citing works
NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink
Ulanovskaya, O. A., Zuhl, A. M., & Cravatt, B. F. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1204 · Cited by 444 · see citing works
Survival and low-grade glioma: the emergence of genetic information
Claus, E. B., Walsh, K. M., Wiencke, J. K., Molinaro, A. M., Wiemels, J. L., Schildkraut, J. M., Bondy, M. L., Berger, M. S., Jenkins, R. B., & Wrensch, M. (2015) · Neurosurgical FOCUS · doi:10.3171/2014.10.focus12367 · Cited by 445 · see citing works
Glioblastoma targeted therapy: updated approaches from recent biological insights
Touat, M., Idbaïh, A., Sanson, M., & Ligon, K. L. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx106 · Cited by 443 · see citing works
Maddocks, O. D. K., Labuschagne, C. F., Adams, P. D., & Vousden, K. H. (2016) · Molecular Cell · doi:10.1016/j.molcel.2015.12.014 · Cited by 440 · see citing works
Clinical practice guidelines for the management of adult diffuse gliomas
Jiang, T., Nam, D., Ram, Z., Poon, W. S., Wang, J., Boldbaatar, D., Mao, Y. Q., Ma, W., Mao, Q., You, Y., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.10.050 · Cited by 431 · see citing works
Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion
Tateishi, K., Wakimoto, H., Iafrate, A. J., Tanaka, S., Loebel, F., Lelic, N., Wiederschain, D., Bedel, O., Deng, G., Zhang, B., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.006 · Cited by 433 · see citing works
MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis
Terunuma, A., Putluri, N., Mishra, P., Mathé, E. A., Dorsey, T. H., Yi, M., Wallace, T. A., Issaq, H. J., Zhou, M., Killian, J. K., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71180 · Cited by 428 · see citing works
Oncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 424 · see citing works
The nexus of chromatin regulation and intermediary metabolism
Gut, P., & Verdin, E. M. (2013) · Nature · doi:10.1038/nature12752 · Cited by 419 · see citing works
Mitochondrial control by DRP1 in brain tumor initiating cells
Xie, Q., Wu, Q., Horbinski, C., Flavahan, W. A., Yang, K., Zhou, W., Dombrowski, S. M., Huang, Z., Fang, X., Shi, Y., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.3960 · Cited by 415 · see citing works
Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas
Kohanbash, G., Carrera, D. A., Shrivastav, S., Ahn, B. J., Jahan, N., Mazor, T., Chheda, Z. S., Downey, K., Watchmaker, P. B., Beppler, C., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90644 · Cited by 412 · see citing works
Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406 · see citing works
Mutant IDH1 regulates the tumor-associated immune system in gliomasPreprint
Amankulor, N., Kim, Y., Arora, S., Kargl, J., Szulzewsky, F., Hanke, M. L., Margineantu, D. H., Rao, A., Bolouri, H., Delrow, J. J., et al. (2017) · Genes & Development · doi:10.1101/gad.294991.116 · Cited by 403 · see citing works
Cairncross, J. G., Wang, M., Jenkins, R. B., Shaw, E. G., Giannini, C., Brachman, D. G., Buckner, J. C., Fink, K., Souhami, L., Laperrière, N., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.49.3726 · Cited by 400 · see citing works
Self-citationCoupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
The implications of IDH mutations for cancer development and therapy
Pirozzi, C. J., & Yan, H. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00521-0 · Cited by 402 · see citing works
The role of enhancers in cancer
Sur, I., & Taipale, J. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.62 · Cited by 382 · see citing works
Miroshnikova, Y. A., Mouw, J. K., Barnes, J. M., Pickup, M. W., Lakins, J. N., Kim, Y., Lobo, K. A., Persson, A. I., Reis, G. F., McKnight, T. R., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3429 · Cited by 384 · see citing works
Targeting glioma stem cells through combined BMI1 and EZH2 inhibition
Jin, X., Kim, L. J. Y., Wu, Q., Wallace, L. C., Prager, B. C., Sanvoranart, T., Gimple, R. C., Wang, X., Mack, S. C., Miller, T. E., et al. (2017) · Nature Medicine · doi:10.1038/nm.4415 · Cited by 379 · see citing works
Gritsch, S., Batchelor, T. T., & Castro, L. N. G. (2021) · Cancer · doi:10.1002/cncr.33918 · Cited by 379 · see citing works
Sex differences in cancer mechanisms
Rubin, J. B., Lagas, J. S., Broestl, L., Sponagel, J., Rockwell, N., Rhee, G., Rosen, S. F., Chen, S., Klein, R. S., Imoukhuede, P. I., et al. (2020) · Biology of Sex Differences · doi:10.1186/s13293-020-00291-x · Cited by 369 · see citing works
Mechanisms regulating T-cell infiltration and activity in solid tumors
Lanitis, E., Dangaj, D., Irving, M., & Coukos, G. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx238 · Cited by 369 · see citing works
The Significance of Mitochondrial Dysfunction in Cancer
Luo, Y., Ma, J., & Lu, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165598 · Cited by 367 · see citing works
Epigenetic Therapeutics: A New Weapon in the War Against Cancer
Ahuja, N., Sharma, A. R., & Baylin, S. B. (2016) · Annual Review of Medicine · doi:10.1146/annurev-med-111314-035900 · Cited by 364 · see citing works
Olar, A., Wani, K. M., Alfaro-Munoz, K. D., Heathcock, L. E., van Thuijl, H. F., Gilbert, M. R., Armstrong, T. S., Sulman, E. P., Cahill, D. P., Vera-Bolanos, E., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1398-z · Cited by 354 · see citing works
Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets
Bi, J., Chowdhry, S., Wu, S., Zhang, W., Masui, K., & Mischel, P. S. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0226-5 · Cited by 348 · see citing works
- Authors
- Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., Campos, C., Fabius, A. W. M., Lu, C., Ward, P. S., Thompson, C. B., Kaufman, A., Guryanova, O., Levine, R., Heguy, A., Viale, A., Morris, L. G. T., Huse, J. T., Mellinghoff, I. K., & Chan, T. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Mellinghoff, Ingo K.
- Chan, Timothy A.
- ORCID
- Venue
- Nature
- Published
- 2012-02-15
- Volume
- 483
- Issue
- 7390
- Pages
- 479-483
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3351699
- OpenAlex
- W1988756388
- Cited by
- 1,974
- References
- 44
- Citations by year
- 2026: 90 · 2025: 92 · 2024: 104 · 2023: 100 · 2022: 136 · 2021: 148 · 2020: 140 · 2019: 142 · 2018: 169 · 2017: 144 · 2016: 163 · 2015: 154 · 2014: 153 · 2013: 152 · 2012: 83
- FWCI
- 82.33
- 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)
- Funders
- National Cancer Institute (F31CA260794, R01CA154767, U54CA143798, P30CA008748)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, glioma, CpG island methylator phenotype, DNA hypermethylation, 2-hydroxyglutarate, oncometabolites, histone demethylation, methylome, astrocytes, gliomagenesis, hypoxia-inducible factor, epigenetic reprogramming
- MeSH terms
- Astrocytes, Cell Survival, Cells, Cultured, Gene Expression Regulation, Glioblastoma, Glioma, Histones, Humans, Isocitrate Dehydrogenase, Mutation, Phenotype, Tumor Cells, Cultured, CpG Islands, DNA Methylation, Epigenesis, Genetic, Metabolome, HEK293 Cells, Epigenomics
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