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Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism
Open accessAbstract
Dysregulation of metabolism is a common phenomenon in cancer cells. The NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) function at a crossroads of cellular metabolism in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction. We review the normal functions of the encoded enzymes, frequent mutations of IDH1 and IDH2 recently found in human cancers, and possible roles for the mutated enzymes in human disease. IDH1 and IDH2 mutations occur frequently in some types of World Health Organization grades 2-4 gliomas and in acute myeloid leukemias with normal karyotype. IDH1 and IDH2 mutations are remarkably specific to codons that encode conserved functionally important arginines in the active site of each enzyme. To date, all IDH1 mutations have been identified at the Arg132 codon. Mutations in IDH2 have been identified at the Arg140 codon, as well as at Arg172, which is aligned with IDH1 Arg132. IDH1 and IDH2 mutations are usually heterozygous in cancer, and they appear to confer a neomorphic enzyme activity for the enzymes to catalyze the production of D-2-hydroxyglutarate. Study of alterations in these metabolic enzymes may provide insights into the metabolism of cancer cells and uncover novel avenues for development of anticancer therapeutics.
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“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [42]
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“This reaction is dependent on Fe as well as a-ketoglutarate; the latter, in turn, is dependent on the activity of either isocitrate dehydrogenase IDH1 in the cytosol and peroxisomes or IDH2 and IDH3 in mitochondria [6,7].”
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“Thus, IDH, instead of generating a-KG, acts on the available a-KG to generate 2-hydroxyglutarate.(129,130) As of yet, it is unclear whether there is also a decrease in a-KG contributing to pathogenesis.”
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“…in IDH1 and IDH2 genes encoding for cytosolic/peroxisomal and mitochondrial nicotinamide adenine dinucleotide phosphate (NADP+)dependent isocitrate dehydrogenases 1 and 2 have been associated with the formation malignant gliomas and acute myeloid leukemia (Dang et al. 2009, Reitman and Yan 2010).”
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“Gross chromosomal anomalies in 1p19q have also been reported in glioma subsets (Reitman and Yan, 2010; Wu et al., 2010).”
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Zjablovskaja, P., & Florian, M. C. (2019) · Cancers · doi:10.3390/cancers12010103 · Cited by 61
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“The enzyme catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate and reduces NAD(P)+ to NAD(P)H (16).”
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“Isocitrate dehydrogenase (ICDH) catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate and is suggested to play a central role in aerobic energy production in the tricarboxylic acid cycle (Reitman and Yan, 2010).”
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“Although both WT IDH1 and IDH2 catalyze the NADP + - dependent oxidation of isocitrate to a -KG, these enzymes probably do not have completely overlapping functions (reviewed in Reitman and Yan 72 ).”
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“…metabolite 2HG (R)-enantiomer are “the drivers” of tumorigenesis, high-grade glioma patients with mutant IDH1/2 usually have better outcomes than those with wild-type IDH1/2 genes (Ahmadi et al., 2012; Ichimura, 2012; Oermann et al., 2012; Reitman and Yan, 2010; Sun et al., 2013; Zhu et al., 2011).”
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“Many studies have shown that the concentrations of 2-HG in glioma cells that harbor IDH1 mutations are 100- to 300-fold greater than those of normal tissue [19].”
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Tee, W.-V., Tan, Z. W., Lee, K., Guarnera, E., & Berezovsky, I. N. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c00540 · Cited by 50
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“A heterozygous mutation at IDH1 codon R132 will cause defective IDH1 enzyme activity which results in a decrease of cellular antioxidant activities (Reitman and Yan, 2010).”
Isocitrate dehydrogenase mutations in diffuse gliomas: clinical and aetiological implications
Gupta, R., Webb-Myers, R., Flanagan, S., & Buckland, M. E. (2011) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2011-200227 · Cited by 49
“Functions of mutant IDH The exact mechanism by which mutations in IDH1 and IDH2 mediate oncogenesis in gliomas is not well understood (figure 4B).(53) 54 68 Two interrelated mechanisms have been proposed: loss of function of IDH enzymes leading to reduced production of a-ketoglutarate and NADPH, and a neomorphic gain…”
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Characterizing Lysine Acetylation of Isocitrate Dehydrogenase in Escherichia coli
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“Due to the important role in generating NADPH for cellular defense against oxidative damage, NADP-dependent ICDHs have been identified to be associated with a number of serious human diseases such as cancer and leukemia [5, 6].”
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p21cip1/waf1 Coordinates Autophagy, Proliferation and Apoptosis in Response to Metabolic Stress
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“In addition to aerobic glycolysis and respiration adaptations, various metabolic changes have been reported in cancer cells, including the dominant expression of pyruvate kinase isozyme M2 (PKM2) in place of PKM1 [132], as well as genetic mutations in succinate dehydrogenase (SDH) [133] and isocitrate dehydrogenase (I…”
BackgroundEvidence of epigenetic alterations in thrombosis and coagulation: A systematic review
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“IDH1 is localized predominantly in cytoplasm and peroxisomes and [8].”
BackgroundInfluentialLoss of IDH2 Accelerates Age-related Hearing Loss in Male Mice
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Down-regulation of IDH2 sensitizes cancer cells to erastin-induced ferroptosis
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“Additionally, the oxidation reaction of TET proteins is dependent on Fe and 2-oxoglutarate (2-OG), and 2-OG is dependent on the activity of isocitrate dehydrogenase IDH1 and IDH2 [5, 6] (Figure S1).”
BackgroundIsocitrate dehydrogenase 2 deficiency aggravates prolonged high-fat diet intake-induced hypertension
Noh, M. R., Kong, M. J., Han, S. J., Kim, J. I., & Park, K. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101548 · Cited by 45
“IDH1 and IDH2 are NADPdependent, and they are found in the cytosol and mitochondria, respectively [22].”
BackgroundInfluentialMalzkorn, B., Wolter, M., Riemenschneider, M. J., & Reifenberger, G. (2011) · Brain Pathology · doi:10.1111/j.1750-3639.2011.00536.x · Cited by 44
“In addition, IDH1 and IDH2 mutations decrease NADPH production (150), probably predisposing cells to oxidative stress (111).”
BackgroundAction at a Distance: Allostery and the Development of Drugs to Target Cancer Cell Metabolism
DeLaBarre, B., Hurov, J., Cianchetta, G., Murray, S., & Dang, L. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.007 · Cited by 45
Janke, R., Iavarone, A. T., & Rine, J. (2017) · eLife · doi:10.7554/elife.22451 · Cited by 40
“In the case of acute myelogenous leukemia, IDH mutations also contribute to progression of these tumors (Molenaar et al., 2014; Reitman and Yan, 2010).”
BackgroundSeneff, S., & Kyriakopoulos, A. M. (2025) · Amino Acids · doi:10.1007/s00726-024-03440-3 · Cited by 43
“Isocitrate, derived from fatty acid β -oxidation, is converted to oxoglutarate (α-ketoglutarate) by mitochondrial isocitrate dehydrogenase, which generates NADPH from NADP + (Reitman & Yan 2010).”
Gong, F., Gao, L., & Ding, T. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.04.069 · Cited by 42
Cagnetta, A., Adamia, S., Acharya, C., Patrone, F., Miglino, M., Nencioni, A., Gobbi, M., & Cea, M. (2014) · Leukemia Research · doi:10.1016/j.leukres.2014.03.006 · Cited by 42
“oth genes function in a crossroads of cellular metabolism, celular defense against oxidative stress, oxidative respiration and xygen-sensing signal transduction [106].”
BackgroundThe Molecular Mechanisms of Resistance to IDH Inhibitors in Acute Myeloid Leukemia
Zhuang, X., Pei, H. Z., Li, T., Huang, J., Guo, Y., Zhao, Y., Yang, M. H., Zhang, D., Chang, Z., Zhang, Q., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.931462 · Cited by 43
Juratli, T. A., Peitzsch, M., Geiger, K. D., Schackert, G., Eisenhofer, G., & Krex, D. (2013) · Neuro-Oncology · doi:10.1093/neuonc/not006 · Cited by 40
Long non‐coding RNAs in cancer metabolism
Xiao, Z., Zhuang, L., & Gan, B. (2016) · BioEssays · doi:10.1002/bies.201600110 · Cited by 40
“Mutations in several metabolic enzymes, most notably isocitrate dehydrogenase 1/2, have been identified in various forms of human cancers, hence evidencing a direct link between metabolism and cancer [2].”
BackgroundModeling APC mutagenesis and familial adenomatous polyposis using human iPS cells
Sommer, C. A., Capilla, A., Molina-Estevez, F. J., Gianotti-Sommer, A., Skvir, N., Caballero, I., Chowdhury, S., & Mostoslavsky, G. (2018) · PLOS ONE · doi:10.1371/journal.pone.0200657 · Cited by 39
“There is a renewed interest in the area of cancer metabolism with metabolic reprogramming coined as a hallmark of cancer based on the discovery of mutations and alterations in IDH1 and IDH2 along with succinate dehydrogenase (SDH), fumarate hydratase (FH), and pyruvate kinase M2 (PKM2) [41, 42].”
BackgroundMapping cancer cell metabolism with 13 C flux analysis: Recent progress and future challenges
Young, J., Duckwall, C., & Murphy, T. A. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.115422 · Cited by 43
“[3-5] These results have also paved the way for broader studies implicating elevated glutamine metabolism[6] and glycine and serine biosynthesis[7-9] in cancer progression, as well as recurrent somatic mutations in mitochondrial enzymes such as isocitrate dehydrogenase (IDH),[10,11] fumarase,[12] and succinate dehydro…”
BackgroundPoinsignon, V., Mercier, L., Nakabayashi, K., David, M. D., Lalli, A., Penard‐Lacronique, V., Quivoron, C., Saada, V., de Botton, S., Broutin, S., et al. (2016) · Journal of Chromatography B · doi:10.1016/j.jchromb.2016.04.030 · Cited by 43
Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia
Ragon, B. K., & Dinardo, C. D. (2017) · Current Hematologic Malignancy Reports · doi:10.1007/s11899-017-0418-6 · Cited by 39
Pyridine Moiety: An Insight into Recent Advances in the Treatment of Cancer
Sahu, R., Mishra, R., Kumar, R., Salahuddin, S., Majee, C., Mazumder, A., & Kumar, A. (2021) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557521666210614162031 · Cited by 39
Elevated citrate in pediatric astrocytomas with malignant progression
Blüml, S., Panigrahy, A., Laskov, M., Dhall, G., Krieger, M. D., Nelson, M., Finlay, J. L., & Gilles, F. H. (2011) · Neuro-Oncology · doi:10.1093/neuonc/nor087 · Cited by 38
Hwang, I., Cao, D., Na, Y., Kim, D.-Y., Zhang, T., Yao, J., Oh, H., HU, J. L., Zheng, H., Yao, Y., et al. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.02.013 · Cited by 38
“…IDH1or 2 mutations (R132H or R172K, respectively) and inactivating mutations in capicua (CIC) on 19q13 (Bettegowda et al., 2011; Hartmann et al., 2010; Ichimura et al., 2009; Parsons et al., 2008; Reitman and Yan, 2010; Sahm et al., 2012; Yan et al., 2009; Yip et al., 2012) in ODGs.”
ALKBH5 ‐induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2
Ji, X., Lv, C., Huang, J., Dong, W., Sun, W., & Zhang, H. (2023) · Cancer Science · doi:10.1111/cas.15772 · Cited by 38
Abreu, P. L., Ferreira, L. M. R., Alpoim, M. C., & Urbano, A. M. (2014) · BioMetals · doi:10.1007/s10534-014-9726-7 · Cited by 39
“It would be interesting to assess, for instance, whether the genes encoding the isocitrate dehydrogenase isoforms IDH1 and IDH2 are affected, as these were found to be mutated in a large variety of tumors (Reitman and Yan 2010).”
BackgroundAltered expression levels of IDH2 are involved in the development of colon cancer
LV, Q., Xing, S., LI, Z., Li, J., Gong, P., Xu, X., CHANG, L., Jin, X., Gao, F., Li, W., et al. (2012) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2012.676 · Cited by 38
“IDH2 and IDH1 mutations occur frequently in certain types of World Health Organization grade 2-4 gliomas and in AML cases with a normal karyotype (18).”
Oizel, K., Gratas, C., Nadaradjane, A., Oliver, L., Vallette, F. M., & Pecqueur, C. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.13 · Cited by 38
“As a result, mutant IDHmay alter the redox state of cells, modulate the activity of metabolic and epigenetic tumor suppressor enzymes that use αKG as a co-substrate.(10) Loss of IDH function may also alter normal mitochondrial function and promote a metabolic switch in cancer cells to glycolysis.”
BackgroundPark, H. Y., Kwon, M. J., Kang, H. S., Kim, Y. J., Kim, N. Y., Kim, M. J., Min, K., Choi, K. C., Nam, E. S., Cho, S. J., et al. (2019) · Human Pathology · doi:10.1016/j.humpath.2019.02.007 · Cited by 37
Endocrine and enzymatic shifts during insect diapause: a review of regulatory mechanisms
Izadi, H. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1544198 · Cited by 36
Evolving Treatment Strategies for Elderly Leukemia Patients with IDH Mutations
Buege, M. J., DiPippo, A. J., & Dinardo, C. D. (2018) · Cancers · doi:10.3390/cancers10060187 · Cited by 35
Tumor dormancy and relapse: understanding the molecular mechanisms of cancer recurrence
Tufail, M., Jiang, C., & Li, N. (2025) · Military Medical Research · doi:10.1186/s40779-025-00595-2 · Cited by 50
Inhibitors of Mutant Isocitrate Dehydrogenases 1 and 2 (mIDH1/2): An Update and Perspective
Ma, T., Zou, F., Pusch, S., Xu, Y., von Deimling, A., & Zha, X. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00159 · Cited by 35
Li, Y., Qin, Q., Zhang, Y., & Cao, Y. (2022) · Current Oncology · doi:10.3390/curroncol29100542 · Cited by 34
“Mutated IDH1 (cytoplasmic peroxidase) and IDH2 (mitochondria) [9] almost completely”
BackgroundThe regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer
Liu, Y., Xu, W., Li, M., Yang, Y., Sun, D., Chen, L., Li, H., & Chen, L. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.12.019 · Cited by 37
NAD(H) and NADP(H) in plants and mammals
Lu, D., Grant, M., & Lim, B. L. (2025) · Molecular Plant · doi:10.1016/j.molp.2025.05.004 · Cited by 35
MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma
Alfardus, H., McIntyre, A., & Smith, S. J. (2017) · BioMed Research International · doi:10.1155/2017/9157370 · Cited by 33
“IDH1 status can also distinguish different glycolytic phenotypes of GBM, which may contribute to the different clinical behaviour of tumours with and without the IDH1 mutations [57].”
BackgroundSu, C., Su, J., Lin, J., Chen, C., Hwang, W., Huang, H. H., & Wu, Y. (2011) · Marine Drugs · doi:10.3390/md9122622 · Cited by 34
“Recently, the importance of IDH in anti-cancer therapeutics has been emphasized [65,66].”
BackgroundKoizume, S., & Miyagi, Y. (2015) · Cancers · doi:10.3390/cancers8010002 · Cited by 36
Graudenzi, A., Maspero, D., Filippo, M. D., Gnugnoli, M., Isella, C., Mauri, G., Médico, E., Antoniotti, M., & Damiani, C. (2018) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2018.09.010 · Cited by 31
Discovery of Novel IDH1 Inhibitor Through Comparative Structure-Based Virtual Screening
Wang, Y., Tang, S., Lai, H., Jin, R., Xu, L., Li, N., Tang, Y., Guo, H., Yao, X., & Leung, E. L. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.579768 · Cited by 33
IDH1 deficiency attenuates gluconeogenesis in mouse liver by impairing amino acid utilization
Ye, J., Gu, Y., Zhang, F., Zhao, Y., Yuan, Y., Hao, Z., Sheng, Y., Li, W. Y., Wakeham, A. C., Cairns, R. A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1618605114 · Cited by 32
Molecular Profile of Intrahepatic Cholangiocarcinoma
Andraus, W., Tustumi, F., Júnior, J. D. D. M., Pinheiro, R. S. N., Waisberg, D. R., Ducatti, L., Arantes, R. M., Rocha‐Santos, V., de Martino, R. B., & D′Albuquerque, L. A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010461 · Cited by 32
“IDH1 and IDH2 play a central role in cellular metabolism, lipid synthesis, and cellular defense against oxygen-free radicals [23].”
BackgroundNADP+-dependent IDH1R132 mutation and its relevance for glioma patient survival
Tewarie, N. M. S. B., Burgers, I. A. V., Dawood, Y., den Boon, H. C., den Brok, M. G. H. E., Klunder, J. H., Koopmans, K. B., Rademaker, E., van den Broek, H. B., van den Bersselaar, S. M., et al. (2013) · Medical Hypotheses · doi:10.1016/j.mehy.2013.02.022 · Cited by 33
White, K., & Someya, S. (2022) · Hearing Research · doi:10.1016/j.heares.2022.108659 · Cited by 30
Hypoxic adaptation of mitochondria and its impact on tumor cell function
Benej, M., Papandreou, I., & Denko, N. C. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.03.004 · Cited by 33
“IDH enzymes exist in three paralogs; homodimeric IDH1 localized in the cytoplasm, homodimeric IDH2 expressed in the mitochondria and NAD + -dependent heterodimeric IDH3 isoform expressed in the mitochondria [115,116].”
BackgroundAtai, N. A., Renkema-Mills, N. A., Bosman, J., Schmidt, N., Rijkeboer, D., Tigchelaar, W., Bosch, K. S., Troost, D., Jonker, A., Bleeker, F. E., et al. (2011) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155411400606 · Cited by 32
“…(6PGDH) is the major NADPH provider in the cytoplasmic compartment of cells, whereas IDH, malate dehydrogenase (MDH), and hexose-6-phosphate dehdrogenase (H6PDH) play a minor role (Van Noorden 1984; Stoward et al. 1991; Koehler and Van Noorden 2003; Kil et al. 2006; Reitman and Yan 2010).”
Background
Metadata
- Authors
- Reitman, Z. J., & Yan, H.
- Affiliations
- Duke University (US)
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-31
- Volume
- 102
- Issue
- 13
- Pages
- 932-941
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC2897878
- OpenAlex
- W2124951199
- Cited by
- 562
- References
- 88
- Citations by year
- 2026: 22 · 2025: 41 · 2024: 20 · 2023: 33 · 2022: 31 · 2021: 44 · 2020: 40 · 2019: 43 · 2018: 40 · 2017: 36 · 2016: 31 · 2015: 34 · 2014: 28 · 2013: 34 · 2012: 38
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Cancer Institute (R01CA118822, R01CA140316)
- National Institute of General Medical Sciences (T32GM007171)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Keywords
- IDH1, IDH2, IDH1 mutation, IDH2 mutation, cancer metabolism, glioma, acute myeloid leukemia, D-2-hydroxyglutarate, oxidative stress, lipogenesis, oxygen sensing, anticancer agents
- MeSH terms
- Animals, Hypoxia, Arginine, Brain Neoplasms, Codon, Glioblastoma, Glucose, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, NADP, Neoplasms, Oligodendroglioma, Oncogenes, Signal Transduction, Up-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor
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