RBCC Red Blood Cell Collection

IDH1 (PICD) [Confidence: low (only semi-automatic identification from reviews)]
Isocitrate dehydrogenase [NADP] cytoplasmic; IDH; 1.1.1.42 (Cytosolic NADP-isocitrate dehydrogenase; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt O75874
ID IDHC_HUMAN Reviewed; 414 AA.
AC O75874; Q567U4; Q6FHQ6; Q7Z3V0; Q93090; Q9NTJ9; Q9UKW8;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JUL-2002, sequence version 2.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Isocitrate dehydrogenase [NADP] cytoplasmic;
DE Short=IDH;
DE EC=1.1.1.42;
DE AltName: Full=Cytosolic NADP-isocitrate dehydrogenase;
DE AltName: Full=IDP;
DE AltName: Full=NADP(+)-specific ICDH;
DE AltName: Full=Oxalosuccinate decarboxylase;
GN Name=IDH1; Synonyms=PICD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9866202;
RA Nekrutenko A., Hillis D.M., Patton J.C., Bradley R.D., Baker R.J.;
RT "Cytosolic isocitrate dehydrogenase in humans, mice, and voles and
RT phylogenetic analysis of the enzyme family.";
RL Mol. Biol. Evol. 15:1674-1684(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=10521434; DOI=10.1074/jbc.274.43.30527;
RA Geisbrecht B.V., Gould S.J.;
RT "The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-
RT dependent isocitrate dehydrogenase.";
RL J. Biol. Chem. 274:30527-30533(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Endometrium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Placenta;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 5-20; 30-49; 101-109; 120-132; 141-212; 223-233;
RP 250-270; 322-338 AND 389-400, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 100-253.
RA Kullmann F., Vogt T., Welsh J., McClelland M.;
RT "Differential gene expression in epithelial cells induced by bile
RT salts: identification by RNA arbitrarily primed PCR.";
RL Submitted (JUN-1996) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-321, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEXES WITH NADP;
RP ISOCITRATE AND CALCIUM IONS, AND SUBUNIT.
RX PubMed=15173171; DOI=10.1074/jbc.M404298200;
RA Xu X., Zhao J., Xu Z., Peng B., Huang Q., Arnold E., Ding J.;
RT "Structures of human cytosolic NADP-dependent isocitrate dehydrogenase
RT reveal a novel self-regulatory mechanism of activity.";
RL J. Biol. Chem. 279:33946-33957(2004).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF VARIANT GBM HIS-132 IN
RP COMPLEX WITH NADP AND ALPHA-KETOGLUTARATE, CATALYTIC ACTIVITY,
RP SUBUNIT, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND CHARACTERIZATION
RP OF VARIANTS CYS-132; HIS-132; LEU-132 AND SER-132.
RX PubMed=19935646; DOI=10.1038/nature08617;
RA Dang L., White D.W., Gross S., Bennett B.D., Bittinger M.A.,
RA Driggers E.M., Fantin V.R., Jang H.G., Jin S., Keenan M.C.,
RA Marks K.M., Prins R.M., Ward P.S., Yen K.E., Liau L.M.,
RA Rabinowitz J.D., Cantley L.C., Thompson C.B., Vander Heiden M.G.,
RA Su S.M.;
RT "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.";
RL Nature 462:739-744(2009).
RN [16]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-132.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [17]
RP VARIANTS HIS-132 AND SER-132.
RX PubMed=18772396; DOI=10.1126/science.1164382;
RA Parsons D.W., Jones S., Zhang X., Lin J.C.-H., Leary R.J.,
RA Angenendt P., Mankoo P., Carter H., Siu I.-M., Gallia G.L., Olivi A.,
RA McLendon R., Rasheed B.A., Keir S., Nikolskaya T., Nikolsky Y.,
RA Busam D.A., Tekleab H., Diaz L.A. Jr., Hartigan J., Smith D.R.,
RA Strausberg R.L., Marie S.K.N., Shinjo S.M.O., Yan H., Riggins G.J.,
RA Bigner D.D., Karchin R., Papadopoulos N., Parmigiani G.,
RA Vogelstein B., Velculescu V.E., Kinzler K.W.;
RT "An integrated genomic analysis of human glioblastoma multiforme.";
RL Science 321:1807-1812(2008).
RN [18]
RP VARIANTS CYS-132; GLY-132 AND LEU-132, AND ROLE IN GLIOMAS.
RX PubMed=19117336; DOI=10.1002/humu.20937;
RA Bleeker F.E., Lamba S., Leenstra S., Troost D., Hulsebos T.,
RA Vandertop W.P., Frattini M., Molinari F., Knowles M., Cerrato A.,
RA Rodolfo M., Scarpa A., Felicioni L., Buttitta F., Malatesta S.,
RA Marchetti A., Bardelli A.;
RT "IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in
RT high-grade gliomas but not in other solid tumors.";
RL Hum. Mutat. 30:7-11(2009).
CC -!- CATALYTIC ACTIVITY: Isocitrate + NADP(+) = 2-oxoglutarate + CO(2)
CC + NADPH.
CC -!- COFACTOR: Binds 1 magnesium or manganese ion per subunit.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=49 uM for NADP;
CC KM=29 uM for magnesium chloride;
CC KM=65 uM for isocitrate;
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Peroxisome.
CC -!- PTM: Acetylation at Lys-374 dramatically reduces catalytic
CC activity (By similarity).
CC -!- DISEASE: Glioma (GLM) [MIM:137800]: Gliomas are benign or
CC malignant central nervous system neoplasms derived from glial
CC cells. They comprise astrocytomas and glioblastoma multiforme that
CC are derived from astrocytes, oligodendrogliomas derived from
CC oligodendrocytes and ependymomas derived from ependymocytes.
CC Note=The gene represented in this entry is involved in disease
CC pathogenesis. Mutations affecting Arg-132 are tissue-specific, and
CC suggest that this residue plays a unique role in the development
CC of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or
CC Ser abolish magnesium binding and abolish the conversion of
CC isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is
CC converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-
CC hydroxyglutarate are correlated with an elevated risk of malignant
CC brain tumors.
CC -!- SIMILARITY: Belongs to the isocitrate and isopropylmalate
CC dehydrogenases family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Isocitrate dehydrogenase entry;
CC URL="http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase";
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DR EMBL; AF020038; AAD02918.1; -; mRNA.
DR EMBL; AF113917; AAD29284.1; -; mRNA.
DR EMBL; AL136702; CAB66637.1; -; mRNA.
DR EMBL; CR541695; CAG46496.1; -; mRNA.
DR EMBL; BX537411; CAD97653.1; -; mRNA.
DR EMBL; AC016697; AAX93221.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70439.1; -; Genomic_DNA.
DR EMBL; BC012846; AAH12846.1; -; mRNA.
DR EMBL; BC093020; AAH93020.1; -; mRNA.
DR EMBL; U62389; AAB17375.1; -; mRNA.
DR PIR; T46280; T46280.
DR RefSeq; NP_001269315.1; NM_001282386.1.
DR RefSeq; NP_001269316.1; NM_001282387.1.
DR RefSeq; NP_005887.2; NM_005896.3.
DR RefSeq; XP_005246578.1; XM_005246521.1.
DR UniGene; Hs.593422; -.
DR PDB; 1T09; X-ray; 2.70 A; A/B=1-414.
DR PDB; 1T0L; X-ray; 2.41 A; A/B/C/D=1-414.
DR PDB; 3INM; X-ray; 2.10 A; A/B/C=1-414.
DR PDB; 3MAP; X-ray; 2.80 A; A/B=1-414.
DR PDB; 3MAR; X-ray; 3.41 A; A/B=1-414.
DR PDB; 3MAS; X-ray; 3.20 A; A/B=1-414.
DR PDB; 4I3K; X-ray; 3.31 A; A/B=1-414.
DR PDB; 4I3L; X-ray; 3.29 A; A/B=1-414.
DR PDB; 4KZO; X-ray; 2.20 A; A/B/C=1-414.
DR PDB; 4L03; X-ray; 2.10 A; A/B/C=1-414.
DR PDB; 4L04; X-ray; 2.87 A; A/B/C/D/E/F=1-414.
DR PDB; 4L06; X-ray; 2.28 A; A/B/C/D/E/F=1-414.
DR PDBsum; 1T09; -.
DR PDBsum; 1T0L; -.
DR PDBsum; 3INM; -.
DR PDBsum; 3MAP; -.
DR PDBsum; 3MAR; -.
DR PDBsum; 3MAS; -.
DR PDBsum; 4I3K; -.
DR PDBsum; 4I3L; -.
DR PDBsum; 4KZO; -.
DR PDBsum; 4L03; -.
DR PDBsum; 4L04; -.
DR PDBsum; 4L06; -.
DR ProteinModelPortal; O75874; -.
DR SMR; O75874; 4-414.
DR DIP; DIP-59311N; -.
DR IntAct; O75874; 4.
DR MINT; MINT-4998878; -.
DR STRING; 9606.ENSP00000260985; -.
DR ChEMBL; CHEMBL2007625; -.
DR PhosphoSite; O75874; -.
DR OGP; O75874; -.
DR REPRODUCTION-2DPAGE; IPI00027223; -.
DR UCD-2DPAGE; O75874; -.
DR PaxDb; O75874; -.
DR PeptideAtlas; O75874; -.
DR PRIDE; O75874; -.
DR DNASU; 3417; -.
DR Ensembl; ENST00000345146; ENSP00000260985; ENSG00000138413.
DR Ensembl; ENST00000415913; ENSP00000390265; ENSG00000138413.
DR Ensembl; ENST00000446179; ENSP00000410513; ENSG00000138413.
DR GeneID; 3417; -.
DR KEGG; hsa:3417; -.
DR UCSC; uc002vcs.3; human.
DR CTD; 3417; -.
DR GeneCards; GC02M209100; -.
DR H-InvDB; HIX0161877; -.
DR HGNC; HGNC:5382; IDH1.
DR HPA; HPA035248; -.
DR MIM; 137800; phenotype.
DR MIM; 147700; gene.
DR neXtProt; NX_O75874; -.
DR Orphanet; 296; Enchondromatosis.
DR Orphanet; 251579; Giant cell glioblastoma.
DR Orphanet; 251576; Gliosarcoma.
DR Orphanet; 163634; Maffucci syndrome.
DR Orphanet; 99646; Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.
DR PharmGKB; PA29630; -.
DR eggNOG; COG0538; -.
DR HOGENOM; HOG000019858; -.
DR HOVERGEN; HBG006119; -.
DR InParanoid; O75874; -.
DR KO; K00031; -.
DR OMA; KELSFFA; -.
DR OrthoDB; EOG7QNVKS; -.
DR PhylomeDB; O75874; -.
DR BioCyc; MetaCyc:HS06502-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; O75874; -.
DR ChiTaRS; IDH1; human.
DR EvolutionaryTrace; O75874; -.
DR GeneWiki; IDH1; -.
DR GenomeRNAi; 3417; -.
DR NextBio; 13470; -.
DR PRO; PR:O75874; -.
DR ArrayExpress; O75874; -.
DR Bgee; O75874; -.
DR CleanEx; HS_IDH1; -.
DR Genevestigator; O75874; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005782; C:peroxisomal matrix; TAS:Reactome.
DR GO; GO:0004450; F:isocitrate dehydrogenase (NADP+) activity; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0050661; F:NADP binding; IEA:Ensembl.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; IDA:UniProtKB.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0008585; P:female gonad development; IEA:Ensembl.
DR GO; GO:0006749; P:glutathione metabolic process; IEA:Ensembl.
DR GO; GO:0006097; P:glyoxylate cycle; IEA:UniProtKB-KW.
DR GO; GO:0006102; P:isocitrate metabolic process; IDA:UniProtKB.
DR GO; GO:0006740; P:NADPH regeneration; TAS:Reactome.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR GO; GO:0048545; P:response to steroid hormone stimulus; IEA:Ensembl.
DR GO; GO:0006099; P:tricarboxylic acid cycle; IEA:UniProtKB-KW.
DR Gene3D; 3.40.718.10; -; 1.
DR InterPro; IPR019818; IsoCit/isopropylmalate_DH_CS.
DR InterPro; IPR004790; Isocitrate_DH_NADP.
DR InterPro; IPR024084; IsoPropMal-DH-like_dom.
DR PANTHER; PTHR11822; PTHR11822; 1.
DR Pfam; PF00180; Iso_dh; 1.
DR PIRSF; PIRSF000108; IDH_NADP; 1.
DR TIGRFAMs; TIGR00127; nadp_idh_euk; 1.
DR PROSITE; PS00470; IDH_IMDH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Glyoxylate bypass; Magnesium; Manganese;
KW Metal-binding; NADP; Oxidoreductase; Peroxisome; Polymorphism;
KW Reference proteome; Tricarboxylic acid cycle.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 414 Isocitrate dehydrogenase [NADP]
FT cytoplasmic.
FT /FTId=PRO_0000083575.
FT NP_BIND 75 77 NADP.
FT NP_BIND 310 315 NADP.
FT REGION 94 100 Substrate binding.
FT METAL 252 252 Magnesium or manganese.
FT METAL 275 275 Magnesium or manganese.
FT BINDING 77 77 Substrate.
FT BINDING 82 82 NADP.
FT BINDING 109 109 Substrate.
FT BINDING 132 132 Substrate.
FT BINDING 260 260 NADP.
FT BINDING 328 328 NADP; via amide nitrogen and carbonyl
FT oxygen.
FT SITE 139 139 Critical for catalysis.
FT SITE 212 212 Critical for catalysis.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 81 81 N6-acetyllysine (By similarity).
FT MOD_RES 224 224 N6-acetyllysine (By similarity).
FT MOD_RES 233 233 N6-acetyllysine (By similarity).
FT MOD_RES 243 243 N6-acetyllysine (By similarity).
FT MOD_RES 321 321 N6-acetyllysine.
FT MOD_RES 374 374 N6-acetyllysine (By similarity).
FT VARIANT 132 132 R -> C (in colorectal cancer and glioma
FT samples; glioblastoma multiforme; somatic
FT mutation; abolishes magnesium binding and
FT alters enzyme activity so that isocitrate
FT is no longer converted to alpha-
FT ketoglutarate but instead alpha-
FT ketoglutarate is converted to R(-)-2-
FT hydroxyglutarate).
FT /FTId=VAR_036013.
FT VARIANT 132 132 R -> G (in a glioma sample; glioblastoma
FT multiforme; somatic mutation).
FT /FTId=VAR_055454.
FT VARIANT 132 132 R -> H (in a glioma sample; glioblastoma
FT multiforme; somatic mutation; abolishes
FT magnesium binding and alters enzyme
FT activity so that isocitrate is no longer
FT converted to alpha-ketoglutarate but
FT instead alpha-ketoglutarate is converted
FT to R(-)-2-hydroxyglutarate).
FT /FTId=VAR_055455.
FT VARIANT 132 132 R -> L (in a glioma sample; glioblastoma
FT multiforme; somatic mutation; abolishes
FT magnesium binding and alters enzyme
FT activity so that isocitrate is no longer
FT converted to alpha-ketoglutarate but
FT instead alpha-ketoglutarate is converted
FT to R(-)-2-hydroxyglutarate).
FT /FTId=VAR_055456.
FT VARIANT 132 132 R -> S (in a glioma sample; glioblastoma
FT multiforme; somatic mutation; abolishes
FT magnesium binding and alters enzyme
FT activity so that isocitrate is no longer
FT converted to alpha-ketoglutarate but
FT instead alpha-ketoglutarate is converted
FT to R(-)-2-hydroxyglutarate).
FT /FTId=VAR_055457.
FT VARIANT 178 178 V -> I (in dbSNP:rs34218846).
FT /FTId=VAR_049780.
FT CONFLICT 32 32 F -> I (in Ref. 3; CAB66637).
FT CONFLICT 126 126 K -> E (in Ref. 3; CAB66637).
FT CONFLICT 172 172 F -> S (in Ref. 5; CAD97653).
FT CONFLICT 174 174 E -> G (in Ref. 5; CAD97653).
FT CONFLICT 218 218 K -> I (in Ref. 1; AAD02918).
FT CONFLICT 307 307 A -> S (in Ref. 6; AAH93020).
FT CONFLICT 329 329 P -> L (in Ref. 1; AAD02918).
FT CONFLICT 381 381 K -> R (in Ref. 1; AAD02918).
FT STRAND 5 14
FT HELIX 17 29
FT TURN 30 34
FT STRAND 35 43
FT HELIX 46 51
FT TURN 52 54
FT HELIX 55 67
FT STRAND 68 72
FT HELIX 80 86
FT HELIX 95 103
FT STRAND 106 111
FT STRAND 128 133
FT HELIX 137 140
FT STRAND 142 146
FT STRAND 148 158
FT STRAND 165 172
FT STRAND 177 185
FT HELIX 186 203
FT STRAND 207 211
FT TURN 213 215
FT HELIX 219 234
FT HELIX 236 241
FT STRAND 246 250
FT HELIX 251 260
FT STRAND 265 269
FT HELIX 271 285
FT STRAND 290 296
FT STRAND 303 309
FT HELIX 313 320
FT HELIX 330 347
FT HELIX 350 369
FT HELIX 374 381
FT HELIX 383 385
FT HELIX 388 390
FT HELIX 394 409
SQ SEQUENCE 414 AA; 46659 MW; 60428B0B6E5851DC CRC64;
MSKKISGGSV VEMQGDEMTR IIWELIKEKL IFPYVELDLH SYDLGIENRD ATNDQVTKDA
AEAIKKHNVG VKCATITPDE KRVEEFKLKQ MWKSPNGTIR NILGGTVFRE AIICKNIPRL
VSGWVKPIII GRHAYGDQYR ATDFVVPGPG KVEITYTPSD GTQKVTYLVH NFEEGGGVAM
GMYNQDKSIE DFAHSSFQMA LSKGWPLYLS TKNTILKKYD GRFKDIFQEI YDKQYKSQFE
AQKIWYEHRL IDDMVAQAMK SEGGFIWACK NYDGDVQSDS VAQGYGSLGM MTSVLVCPDG
KTVEAEAAHG TVTRHYRMYQ KGQETSTNPI ASIFAWTRGL AHRAKLDNNK ELAFFANALE
EVSIETIEAG FMTKDLAACI KGLPNVQRSD YLNTFEFMDK LGENLKIKLA QAKL
//

MIM 137800
*RECORD*
*FIELD* NO
137800
*FIELD* TI
#137800 GLIOMA SUSCEPTIBILITY 1; GLM1
GLIOMA OF BRAIN, FAMILIAL, INCLUDED; GLM, INCLUDED;;
read moreGLIOBLASTOMA MULTIFORME, INCLUDED; GBM, INCLUDED;;
ASTROCYTOMA, INCLUDED;;
OLIGODENDROGLIOMA, INCLUDED;;
EPENDYMOMA, INCLUDED;;
SUBEPENDYMOMA, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because glioma can develop as
part of Li-Fraumeni syndrome-1 (LFS1; 151623), a cancer predisposition
syndrome caused by mutation in the TP53 gene (191170) on chromosome
17p13.

DESCRIPTION

Gliomas are central nervous system neoplasms derived from glial cells
and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas,
ependymomas, and subependymomas. Glial cells can show various degrees of
differentiation even within the same tumor (summary by Kyritsis et al.,
2010).

Ependymomas are rare glial tumors of the brain and spinal cord (Yokota
et al., 2003).

Subependymomas are unusual tumors believed to arise from the bipotential
subependymal cell, which normally differentiates into either ependymal
cells or astrocytes. They were characterized as a distinct entity by
Scheinker (1945). They tend to be slow-growing, noninvasive, and located
in the ventricular system, septum pellucidum, cerebral aqueduct, or
proximal spinal cord (summary by Ryken et al., 1994).

Gliomas are known to occur in association with several other
well-defined hereditary tumor syndromes such as mismatch repair cancer
syndrome (276300), melanoma-astrocytoma syndrome (155755),
neurofibromatosis-1 (NF1; 162200) and NF2 (101000), and tuberous
sclerosis (TSC1; 191100). Familial clustering of gliomas may occur in
the absence of these tumor syndromes, however.

- Genetic Heterogeneity of Susceptibility to Glioma

Germline mutations predisposing to glioma have also been identified in
the PTEN (601728) gene on chromosome 10q23.31 (GLM2; 613028) and in the
BRCA2 gene (600185) on chromosome 13q12.3 (GLM3; 613029).

Loci associated with susceptibility to glioma have been identified on
chromosomes 15q23-q26.3 (GLM4; 607248), 9p21.3 (GLM5; 613030), 20q13.33
(GLM6; 613031), 8q24.21 (GLM7; 613032), and 5p15.33 (GLM8; 613033).

Somatic mutation, disruption, or copy number variation of the following
genes or loci may also contribute to the formation of glioma: ERBB
(EGFR; 131550), ERBB2 (164870), LGI1 (604619), GAS41 (602116), GLI
(165220), DMBT1 (601969), IDH1 (147700), IDH2 (147650), BRAF (164757),
PARK2 (602544), TP53 (191170), RB1 (614041), PIK3CA (171834), 10p15,
19q, and 17p13.3.

INHERITANCE

King and Eisinger (1966) described glioma multiforme of the frontal
lobes in father and daughter with development of symptoms at age 50 and
34 years, respectively. Armstrong and Hanson (1969) described 3 sibs who
died of brain glioma in adulthood. In a study of cancer mortality during
childhood in sibs, Miller (1971) found 8 pairs of nontwin sibs with
brain tumor versus 0.9 expected. There were 8 other families versus 0.9
expected in which 1 child died of brain tumor and another died of cancer
of bone or muscle. Thuwe et al. (1979) observed 6 cases of brain glioma
and a possible seventh on an isolated Swedish coastal island. The
affected persons were related as cousins, all in different sibships. One
instance of parental consanguinity, the lack of parent-child
transmission, and the longtime isolation of the population suggest
recessive inheritance. In further studies in this island community,
Thuwe (1984) reported 4 closely related cases of brain tumor. It was
found that 30 probands with brain tumor were more often the product of a
consanguineous marriage than were controls and a higher proportion could
be traced to a common ancestor living in the 1600s. It was concluded
that genetic factors play a role, although a single major gene seemed
unlikely.

Schianchi and Kraus-Ruppert (1980) described affected father and son,
suggesting autosomal dominant inheritance.

In a highly inbred Arab family in Israel, Chemke et al. (1985) observed
5 cases of glioblastoma multiforme in 2 sibships. Curiously, all were
male and in all the tumor was located on the right side of the brain.
The ages of presentation ranged from 4 to 11 years. 'Astrocytoma type 3'
was the histologic diagnosis.

Leblanc et al. (1986) described father and son operated on at ages 26
and 37 years, respectively, for mixed oligodendrocytic-astrocytic
glioma. Heuch and Blom (1986) reported glioblastoma multiforme in 2
brothers, aged 65 and 68 years, and in their paternal aunt, aged 81. The
father had died of tuberculosis before age 40. True multicentric origin,
consistent with a hereditary basis, was observed in 1 of the 3 cases.

Clarenbach et al. (1979) described the simultaneous occurrence of fourth
ventricular subependymomas in monozygotic twins, both of whom became
symptomatic at 22 years of age. Honan et al. (1987) described
subependymomas in 3 out of 11 sibs. Ryken et al. (1994) reported the
occurrence of fourth ventricular subependymomas in a father and son.

Tijssen (1987) referred to an international register of familial brain
tumors maintained in Leyden. Vieregge et al. (1987) gave an extensive
review of reported cases of familial glioma with or without other
malformations. They reported a family in which members of several
generations had one or another abnormality: father and son had glioma;
another man and his daughter had colonic polyps; and skeletal
abnormalities in the form of short stature and exostoses were present in
some members. Munoz et al. (1988) described a brother and sister without
a history of phacomatosis or cerebral tumors who developed malignant
tumors with ependymal and choroidal differentiation. The girl presented
at 28 months with a tumor of the posterior fossa, and the boy presented
at 15 months with a tumor of the left cerebral hemisphere. Duhaime et
al. (1989) reported histologically identical glioblastoma multiforme in
2 sibs, aged 2 and 5 years, whose symptoms developed simultaneously.

On the basis of segregation analyses in families with multiple glioma
patients, autosomal recessive and multifactorial mendelian models have
been suggested (Malmer et al., 2001; de Andrade et al., 2001).

In a review of the Utah population database for individuals with primary
brain tumors, including 744 astrocytomas and 658 glioblastomas,
Blumenthal and Cannon-Albright (2008) found significant excess of
affected first-degree relatives among patients with astrocytomas and
glioblastomas as a group (relative risk (RR) of 3.29) and for
astrocytomas (RR of 3.82) and glioblastomas (RR of 2.29) considered
separately. Among second-degree relatives, only astrocytoma showed a
significant RR of 1.91 (p = 0.03). Analysis of the data using a
genealogic index of familiarity (GIF) showed significant excess
relatedness for astrocytomas and glioblastomas as a group and for the
astrocytoma subgroup, but not for the glioblastoma subgroup. The results
suggested that there is a strongly heritable contribution to astrocytoma
risk and nominal contribution to glioblastoma risk.

DIAGNOSIS

Marie et al. (2001) found that OLIG2 (606386) expression was upregulated
in neoplastic oligodendrocytes, but not in neoplastic astrocytes or in
other brain tumor cells, and suggested its use as a specific marker in
the diagnosis of oligodendroglial tumors.

- Prenatal Diagnosis

The case of prenatal diagnosis ascertained via ultrasound reported by
Geraghty et al. (1989) illustrated the occurrence of glioblastoma
multiforme in the fetus.

PATHOGENESIS

Von Deimling et al. (1995) proposed a simplified model for the
pathogenesis of human gliomas. Reviewing their work and that of others,
they suggested 3 distinct pathways. The first pathway, which leads to
pilocytic astrocytomas (WHO grade I), is caused by loss of
heterozygosity for chromosome 17q, presumably unmasking mutations in the
NF1 (613113) gene. The second pathway begins with LOH at 17p, unmasking
mutations in p53 (191170) and leading to astrocytoma (WHO grade II).
Further LOH at 13q, 19q and 9p, unmasking mutations in RB1 (614041), p16
and p15, provides a further step on the second pathway, giving rise to
grade III astrocytomas. The final step on the second pathway, LOH on
chromosome 10 and perhaps other chromosomes, culminates in glioblastoma
multiforme type 1 (WHO grade IV). The third independent pathway begins
with LOH at chromosomes 10 and 9p, followed by gene amplification of
EGFR (131550), CDK4 (123829), MDM2 (164785), and SAS (181035), and
culminating in glioblastoma multiforme type 2 (WHO grade IV).

Bogler et al. (1995) reviewed the role of the p53 gene in the initiation
and progression of human gliomas. Pollack et al. (2002) found that
overexpression of p53 in malignant gliomas during childhood was strongly
associated with an adverse outcome, independent of clinical prognostic
factors and histologic findings.

By gene expression profiling, Liang et al. (2005) found significant
upregulation of genes involved in macrophage activation, hypoxia,
extracellular matrix remodeling, and cell proliferation from 25
different glioblastoma multiforme specimens compared to normal brain
tissue. These findings paralleled the histologic observations of
macrophage infiltration, tissue necrosis, tumor vasculature, and
proliferation of tumor cells. Gene expression patterns were always more
closely related to different specimens from the same tumor than to that
of any other tumor, suggesting molecular heterogeneity between tumors.
Immunohistochemical studies confirmed increased expression of the FABP7
gene (602965), known to be involved in the establishment of the radial
glial system in the developing brain, and showed that expression was
associated with decreased survival, particularly in younger patients, in
2 unrelated cohorts totaling 105 patients. Transfection of FABP7 into
glioma cells in vitro resulted in a 5-fold increase in cell migration
compared to control cells, suggesting a functional correlation.

Bao et al. (2006) showed that cancer stem cells contribute to glioma
radioresistance through preferential activation of the DNA damage
checkpoint response and an increase in DNA repair capacity. The fraction
of tumor cells expressing CD133 (604365), a marker for both neural stem
cells and brain cancer stem cells, was enriched after radiation in
gliomas. In both cell culture and the brains of immunocompromised mice,
CD133-expressing glioma cells survived ionizing radiation in increased
proportions relative to most tumor cells, which lack CD133.
CD133-expressing tumor cells isolated from both human glioma xenografts
and primary patient glioblastoma specimens preferentially activated the
DNA damage checkpoint in response to radiation, and repaired
radiation-induced DNA damage more effectively than CD133-negative tumor
cells. In addition, Bao et al. (2006) found that the radioresistance of
CD133-positive glioma stem cells could be reversed with a specific
inhibitor of the CHK1 (603078) and CHK2 (604373) checkpoint kinases. Bao
et al. (2006) concluded that CD133-positive tumor cells represent the
cellular population that confers glioma radioresistance and could be the
source of tumor recurrence after radiation. Targeting DNA damage
checkpoint response in cancer stem cells may overcome this
radioresistance and provide a therapeutic model for malignant brain
cancers.

Piccirillo et al. (2006) reported that bone morphogenic proteins (BMPs),
among which BMP4 (112262) elicits the strongest effect, trigger a
significant reduction in the stem-like, tumor-initiating precursors of
human glioblastomas. Transient in vitro exposure to BMP4 abolished the
capacity of transplanted glioblastoma cells to establish intracerebral
glioblastomas. Most importantly, in vivo delivery of BMP4 effectively
blocked the tumor growth and associated mortality that occurred in 100%
of mice after intracerebral grafting of human glioblastoma cells.
Piccirillo et al. (2006) demonstrated that BMPs activate their cognate
receptor BMPRs and trigger the SMAD (see 601595) signaling cascade in
cells isolated from human glioblastomas. This is followed by a reduction
in proliferation, and increased expression of markers of neural
differentiation, with no effect on cell viability. The concomitant
reduction in clonogenic ability, in the size of the CD133-positive
population, and in the growth kinetics of glioblastoma cells indicated
that BMP4 reduces the tumor-initiating cell pool of glioblastomas. These
findings showed that the BMP-BMPR signaling system, which controls the
activity of normal brain stem cells, may also act as a key inhibitory
regulator of tumor-initiating, stem-like cells from glioblastomas. The
results also identified BMP4 as a novel, noncytotoxic therapeutic
effector, which may be used to prevent growth and recurrence of
glioblastomas in humans.

Savaskan et al. (2008) found that human primary gliomas showed increased
expression of XCT, encoded by the SLC7A11 gene (607933), that was
associated with increased glutamate secretion compared to normal brain
tissue. Further studies suggested that gliomas secrete glutamate via XCT
channels, thereby causing neuronal cell death. Genetic or pharmacologic
inhibition of Xct in rats with gliomas abrogated neurodegeneration,
attenuated perifocal edema, and prolonged survival. These findings
indicated a crucial role for XCT in glioma-induced neurodegeneration and
brain edema, corroborating the concept that edema formation may be in
part a consequence of peritumoral cell death.

Carro et al. (2010) used reverse engineering and an unbiased
interrogation of a glioma-specific regulatory network to reveal the
transcriptional module that activates expression of mesenchymal genes in
malignant glioma. Two transcription factors, C/EBP-beta (189965) and
STAT3 (102582), emerged as synergistic initiators and master regulators
of mesenchymal transformation. Ectopic coexpression of C/EBP-beta and
STAT3 reprogrammed neural stem cells along the aberrant mesenchymal
lineage, whereas elimination of the 2 factors in glioma cells led to
collapse of the mesenchymal signature and reduced tumor aggressiveness.
In human glioma, expression of C/EBP-beta and STAT3 correlated with
mesenchymal differentiation and predicted poor clinical outcome. Carro
et al. (2010) concluded that the activation of a small regulatory module
is necessary and sufficient to initiate and maintain an aberrant
phenotypic state in cancer cells.

Sheng et al. (2010) used a genomewide RNAi screen in mouse glioma cells
to identify activators of the transcription factor ATF5 (606398), which
is highly expressed in glioma cells. The results indicated that FRS2
(607743), PAK1 (602590), and CREB3L2 (608834) are components of
RAS-MAPK- or PI3K-activated pathways that regulate ATF5 expression, and
that this pathway is required for viability of malignant glioma cells.
Further studies indicated that ATF5 promoted survival through
upregulation of MCL1 (159552), an antiapoptotic factor. The ATF5 pathway
was also found to promote survival in other human cancer cell lines.
Analysis of human malignant glioma samples indicated that ATF5
expression inversely correlated with disease prognosis. The RAF kinase
inhibitor sorafenib suppressed ATF5 expression in glioma stem cells and
inhibited malignant glioma growth in human cell culture and mouse
models. The findings demonstrated that ATF5 is essential in genesis of
malignant glioma.

Ricci-Vitiani et al. (2010) showed that a variable number (20 to 90%,
mean 60.7%) of endothelial cells in glioblastoma carry the same genomic
alteration as tumor cells, indicating that a significant portion of the
vascular endothelium has a neoplastic origin. The vascular endothelium
contained a subset of tumorigenic cells that produced highly
vascularized anaplastic tumors with areas of vasculogenic mimicry in
immunocompromised mice. In vitro culture of glioblastoma stem cells in
endothelial conditions generated progeny with phenotypic and functional
features of endothelial cells. Likewise, orthotopic or subcutaneous
injection of glioblastoma stem cells in immunocompromised mice produced
tumor xenografts, the vessels of which were primarily composed of human
endothelial cells. Selective targeting of endothelial cells generated by
glioblastoma stem cells in mouse xenografts resulted in tumor reduction
and degeneration, indicating the functional relevance of the
glioblastoma stem cell-derived endothelial vessels. Ricci-Vitiani et al.
(2010) concluded that their findings described a novel mechanism for
tumor vasculogenesis and may explain the presence of cancer-derived
endothelial-like cells in several malignancies.

Wang et al. (2010) independently demonstrated that a subpopulation of
endothelial cells within glioblastomas harbor the same somatic mutations
identified within tumor cells. In addition, the authors demonstrated
that the stem cell-like CD133 (604365)-positive fraction includes a
subset of vascular endothelial cadherin (CD144)-expressing cells that
show characteristics of endothelial progenitors capable of maturation
into endothelial cells. Extensive in vitro and in vivo lineage analyses,
including single cell clonal studies, further showed that a
subpopulation of the CD133-positive stem-like cell fraction is
multipotent and capable of differentiation along tumor and endothelial
lineages, possibly via an intermediate CD133-positive/CD144-positive
progenitor cell. Wang et al. (2010) asserted that their findings were
supported by genetic studies of specific exons selected from the Cancer
Genome Atlas, quantitative FISH, and comparative genomic hybridization
data that demonstrated identical genomic profiles in the CD133-positive
tumor cells, their endothelial progenitor derivatives, and mature
endothelium. Exposure to the clinical antiangiogenesis agent bevacizumab
or to a gamma-secretase inhibitor as well as knockdown small hairpin RNA
(shRNA) studies demonstrated that blocking VEGF (192240) or silencing
VEGFR2 (191306) inhibits the maturation of tumor endothelial progenitors
into endothelium but not the differentiation of CD133-positive cells
into endothelial progenitors, whereas gamma-secretase inhibition or
NOTCH1 (190198) silencing blocks the transition into endothelial
progenitors. Wang et al. (2010) concluded that their data provided novel
perspectives on the mechanisms of failure of antiangiogenesis
inhibitors. The lineage plasticity and capacity to generate tumor
vascularization of the putative cancer stem cells within glioblastoma
were novel findings that provided insight into the biology of gliomas
and the definition of cancer stemness, as well as the mechanisms of
tumor neoangiogenesis.

Johnson et al. (2010) identified subgroups of human ependymoma and then
performed genomic analyses and found subgroup-specific alterations that
included amplifications and homozygous deletions of genes not previously
implicated in ependymoma. They then used cross-species genomics to
select cellular compartments most likely to give rise to subgroups of
ependymoma and compared human tumors and mouse neural stem cells,
isolated from different regions, specifically with an intact or deleted
Cdkn2a (600160)/Cdkn2b (600431) locus. The transcriptome of human
supratentorial ependymomas with amplified EPHB2 (600997) and deleted
CDKN2A/CDKN2B matched only that of embryonic cerebral Cdkn2a/Cdkn2b -/-
mouse neuronal stem cells. Activation of Ephb2 signaling in
Cdkn2a/Cdkn2b -/- mouse neuronal stem cells, but not other neural stem
cells, generated the first mouse model of ependymoma, which was highly
penetrant and accurately modeled the histology and transcriptome of 1
subgroup of human supratentorial tumor (subgroup D). Comparative
analysis of matched mouse and human tumors revealed selective
deregulation in the expression and copy number of genes that control
synaptogenesis, pinpointing disruption of this pathway as a critical
event in the production of this ependymoma subgroup.

Singh et al. (2012) reported that a small subset of GBMs (3.1%; 3 of 97
tumors examined) harbors oncogenic chromosomal translocations that fuse
in-frame the tyrosine kinase coding domains of fibroblast growth factor
receptor (FGFR) genes (FGFR1, 136350 or FGFR3, 134934) to the
transforming acidic coiled-coil (TACC) coding domains of TACC1 (605301)
or TACC3 (605303), respectively. The FGFR-TACC fusion protein displayed
oncogenic activity when introduced into astrocytes or stereotactically
transduced in the mouse brain. The fusion protein, which localizes to
mitotic spindle poles, has constitutive kinase activity and induces
mitotic and chromosomal segregation defects and triggers aneuploidy.
Inhibition of FGFR kinase corrected the aneuploidy, and oral
administration of an FGFR inhibitor prolonged survival of mice harboring
intracranial FGFR3-TACC3-initiated glioma. Singh et al. (2012) concluded
that FGFR-TACC fusions could potentially identify a subset of GBM
patients who would benefit from targeted FGFR kinase inhibition.

- Pediatric Glioblastoma

Schwartzentruber et al. (2012) sequenced the exomes of 48 pediatric
glioblastoma samples. Somatic mutations in the H3.3-ATRX (300032)-DAXX
(603186) chromatin remodeling pathway were identified in 44% of tumors
(21 of 48). Recurrent mutations in H3F3A (601128), which encodes the
replication-independent histone-3 variant H3.3, were observed in 31% of
tumors, and led to amino acid substitutions at 2 critical positions
within the histone tail (K27M, G34R/G34V) involved in key regulatory
posttranslational modifications. Mutations in ATRX and DAXX, encoding 2
subunits of a chromatin remodeling complex required for H3.3
incorporation at pericentric heterochromatin and telomeres, were
identified in 31% of samples overall, and in 100% of tumors harboring a
G34R or G34V H3.3 mutation. Somatic TP53 (191170) mutations were
identified in 54% of all cases, and in 86% of samples with H3F3A and/or
ATRX mutations. Screening of a large cohort of gliomas of various grades
and histologies (n = 784) showed H3F3A mutations to be specific to
glioblastoma multiforme and highly prevalent in children and young
adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was
strongly associated with alternative lengthening of telomeres and
specific gene expression profiles. Schwartzentruber et al. (2012) stated
that this was the first report to highlight recurrent mutations in a
regulatory histone in humans, and concluded that their data suggested
that defects of the chromatin architecture underlie pediatric and young
adult glioblastoma multiforme pathogenesis.

Wu et al. (2012) reported that a K27M mutation occurring in either H3F3A
or HIST1H3B (602819) was observed in 78% of diffuse intrinsic pontine
gliomas (DIPGs) and 22% of non-brain-stem gliomas.

Lewis et al. (2013) reported that human (DIPGs) containing the K27M
mutation in either histone H3.3 (H3F3A) or H3.1 (HIST1H3B) display
significantly lower overall amounts of H3 with trimethylated lysine-27
(H3K27me3) and that histone H3K27M transgenes are sufficient to reduce
the amounts of H3K27me3 in vitro and in vivo. Lewis et al. (2013) found
that H3K27M inhibits the enzymatic activity of the Polycomb repressive
complex-2 (PRC2) through interaction with the EZH2 (601573) subunit. In
addition, transgenes containing lysine-to-methionine substitutions at
other known methylated lysines (H3K9 and H3K36) are sufficient to cause
specific reduction in methylation through inhibition of SET domain
enzymes. Lewis et al. (2013) proposed that K-to-M substitutions may
represent a mechanism to alter epigenetic states in a variety of
pathologies.

- Pilocytic Astrocytoma

Jones et al. (2013) described whole-genome sequencing of 96 pilocytic
astrocytomas, with matched RNA sequencing for 73 samples, conducted by
the International Cancer Genome Consortium PedBrain Tumor Project. Jones
et al. (2013) identified recurrent activating mutations in FGFR1 and
PTPN11 (176876) and novel NTRK2 (600456) fusion genes in noncerebellar
tumors. Novel BRAF (164757)-activating changes were also observed. MAPK
pathway alterations affected all tumors analyzed, with no other
significant mutations identified, indicating that pilocytic astrocytoma
is predominantly a single-pathway disease. Notably, Jones et al. (2013)
identified the same FGFR1 mutations in a subset of H3F3A
(601128)-mutated pediatric glioblastoma with additional alterations in
the NF1 gene (613113).

CYTOGENETICS

Gilchrist and Savard (1989) described the familial occurrence of
ependymoma in 2 sisters and a maternal male cousin. Karyotypic analysis
of the tumor from 1 sister showed mosaicism for the loss of one
chromosome 22.

Approximately 30% of ependymomas are said to have monosomy 22 as
revealed by cytogenetic studies (Griffin et al., 1992; Ransom et al.,
1992; Sainati et al., 1992).

Yokota et al. (2003) reported a non-neurofibromatosis type II (101000)
Japanese family in which 2 of 4 sibs had cervical spinal cord ependymoma
and 1 of the 4 had schwannoma. Loss of heterozygosity (LOH) studies in 2
of the patients showed a common allelic loss at 22q11.2-qter. The
findings suggested the existence of a tumor suppressor gene on
chromosome 22 related to the tumorigenesis of familial ependymal tumors.
The NF2 gene (607379) maps to chromosome 22q12.

MOLECULAR GENETICS

Kyritsis et al. (1994) identified germline mutations in the TP53 gene
(see, e.g., 191170.0042) in 6 of 19 patients with multifocal glioma, all
of whom had a family history of cancer. In addition, germline TP53
mutations were found in 3 of 19 patients with unifocal glioma and a
family history of cancer. No mutations were detected in a patient with
unifocal glioma and another malignancy or in 12 control patients with
unifocal glioma and no second malignancies or family history of cancer.
Patients with mutations were younger than other patients in the same
group. Kyritsis et al. (1994) concluded that germline TP53 mutations are
frequent in patients with multifocal glioma, glioma and another primary
malignancy, and glioma associated with a family history of cancer,
particularly if these factors are combined.

Chen et al. (1995) found somatic mutations in the TP53 gene in 8 of 22
adult glioma tissue specimens and germline mutations in 2 of these 8
patients. Both patients with germline mutations developed glioblastoma
multiforme before the age of 31, compared to the median age of greater
than 50 for glioma patients. Family history was not available for these
patients. TP53 mutations were not found in 16 glial tumors occurring in
children or in benign meningiomas. The findings suggested that TP53
germline mutations may identify a subset of young adults predisposed to
the development of high-grade astrocytic tumors.

In a family in which several individuals had glioblastome multiforme and
additional family members had multiple cancer types including some
consistent with Li-Fraumeni syndrome (151623), Tachibana et al. (2000)
identified a germline mutation in the p53 gene (R248Q; 191170.0010). The
authors concluded that point mutations of p53 may be responsible for
some apparent familial glioma cases.

- Modifier Genes

Among 254 patients with glioblastoma multiforme, El Hallani et al.
(2009) found an association between a pro72 allele in the TP53 gene
(191170.0005) and earlier age at onset. The pro/pro genotype was present
in 20.6% of patients with onset before age 45 years compared to in 6.5%
of those with onset after age 45 years (p = 0.002) and 5.9% among 238
controls (p = 0.001). The findings were confirmed in an additional
cohort of 29 patients. The variant did not have any impact on overall
patient survival. Analysis of tumor DNA from 73 cases showed an
association between the pro allele and a higher rate of somatic TP53
mutations.

- Somatic Mutations

To identify the genetic alterations in glioblastoma multiforme (GBM),
Parsons et al. (2008) sequenced 20,661 protein-coding genes, determined
the presence of amplifications and deletions using high-density
oligonucleotide arrays, and performed gene expression analyses using
next-generation sequencing technologies in 22 human tumor samples. This
comprehensive analysis led to the discovery of a variety of genes that
were not known to be altered in GBMs. Most notably, Parsons et al.
(2008) found recurrent mutations in the active site of isocitrate
dehydrogenase-1 (IDH1; 147700) in 12% of GBM patients. Mutations in IDH1
occurred in a large fraction of young patients and in most patients with
secondary GBMs and were associated with an increase in overall survival.
Parsons et al. (2008) concluded that their studies demonstrated the
value of unbiased genomic analyses in the characterization of human
brain cancer and identified a potentially useful genetic alteration for
the classification and targeted therapy of GBMs. Parsons et al. (2008)
found that the hazard ratio for death among 79 patients with wildtype
IDH1, as compared to 11 with mutant IDH1, was 3.7 (95% confidence
interval, 2.1 to 6.5; p less than 0.001). The median survival was 3.8
years for patients with mutated IDH1, as compared to 1.1 years for
patients with wildtype IDH1. Parsons et al. (2008) found that a majority
of tumors analyzed had alterations in genes encoding components of each
of the TP53 (191170), RB1 (614041), and PI3K (see 171834) pathways.

The Cancer Genome Atlas Research Network (2008) reported the interim
integrative analysis of DNA copy number, gene expression, and DNA
methylation aberrations in 206 glioblastomas and nucleotide sequence
alterations in 91 of the 206 glioblastomas. The authors found that p53
itself showed mutation or homozygous deletion in 35% of tumors and that
there was altered p53 signaling in 87% of tumors, as demonstrated by
homozygous deletion or mutations in CDKN2A (600160) in 49% of tumors,
amplification of MDM2 (164785) in 14%, and amplification of MDM4
(602704) in 7%. The authors also observed that the RTK/RAS/PI3K
signaling pathway was altered in 88% of glioblastomas. EGFR (131550)
mutation or amplification was present in 45%, PDGFRA (173490)
amplification was present in 13%, and MET (164860) amplification was
present in 4%. (ERBB2 (164870) mutation was reported in 8%; in an
erratum, the group stated that the somatic mutations reported in ERBB2
were actually an artifact of DNA amplification and were not validated in
unamplified DNA.) Furthermore, NF1 (613113) was found to be an important
gene in glioblastoma as mutation or homozygous deletion of the NF1 gene
was present in 18% of tumors. Somatic mutation in the PI3K complex was
frequently identified. In particular, novel somatic mutations were
identified in the PIK3R1 gene (171833) that result in disruption of the
important C2-iSH2 interaction between PIK3R1 and PIK3CA (171834). The RB
signaling pathway was found to be altered in 78% of glioblastomas, with
RB itself mutated in 11% of tumors. Of note, the Cancer Genome Atlas
Research Network (2008) found a link between MGMT (156569) promoter
methylation and hypermutator phenotype consequent to mismatch repair
deficiency in treated glioblastomas. The methylation status of MGMT
predicts sensitivity to temozolomide, an alkylating agent used to treat
glioblastoma patients. In those patients who also have mutation in the
mismatch repair pathway, treatment with an alkylating agent was
associated with characteristic C-G and A-T transitions in non-CpG sites,
raising the possibility that patients who initially respond to treatment
with alkylating agents may evolve not only treatment resistance but also
a mismatch repair-defective hypermutator phenotype.

Bredel et al. (2011) analyzed 790 human glioblastomas for deletions,
mutations, or expression of NFKBIA (164008) and EGFR. They further
studied the tumor suppressor activity of NFKBIA in tumor cell culture
and compared the molecular results with the outcome of glioblastoma in
570 affected individuals. Bredel et al. (2011) found that NFKBIA is
often deleted but not mutated in glioblastomas; most deletions occur in
nonclassical subtypes of the disease. Deletion of NFKBIA and
amplification of EGFR show a pattern of mutual exclusivity. Restoration
of the expression of NFKBIA attenuated the malignant phenotype and
increased the vulnerability to chemotherapy of cells cultured from
tumors with NFKBIA deletion; it also reduced the viability of cells with
EGFR amplification but not of cells with normal gene dosages of both
NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated
with unfavorable outcomes. Patients who had tumors with NFKBIA deletion
had outcomes that were similar to those in patients with tumors
harboring EGFR amplification. These outcomes were poor as compared with
the outcomes in patients with tumors that had normal gene dosages of
NFKBIA and EGFR. Bredel et al. (2011) suggested a 2-gene model that was
based on expression of NFKBIA and O(6)-methylguanine DNA
methyltransferase (156569) being strongly associated with the clinical
course of the disease, and concluded that deletion of NFKBIA has an
effect that is similar to the effect of EGFR amplification in the
pathogenesis of glioblastoma and is associated with comparatively short
survival.

- Mutations in IDH1 and IDH2

Yan et al. (2009) determined the sequence of the IDH1 (147700) gene and
related IDH2 (147650) gene in 445 CNS tumors and 494 non-CNS tumors. The
enzymatic activity of the proteins that were produced from normal and
mutant IDH1 and IDH2 genes was determined in cultured glioma cells that
were transfected with these genes. Yan et al. (2009) identified
mutations that affected amino acid 132 of IDH1 in more than 70% of World
Health Organization (WHO) grade II and III astrocytomas and
oligodendrogliomas and in glioblastomas that developed from these
lower-grade lesions. Tumors without mutations in IDH1 often had
mutations affecting the analogous amino acid (R172) of the IDH2 gene.
Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical
characteristics, and patients with such tumors had a better outcome than
those with wildtype IDH genes. Each of the 4 tested IDH1 and IDH2
mutations reduced the enzymatic activity of the encoded protein. Yan et
al. (2009) concluded that mutations of NADP(+)-dependent isocitrate
dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several
types of malignant gliomas.

De Carli et al. (2009) found that IDH1 mutations were more commonly
found in adult patients with gliomas (38%; 155 of 404) compared to
children with gliomas (5%; 4 of 73). No IDH2 mutations were found in 73
children with gliomas. IDH1 mutations in adults were significantly
associated with lower tumor grade, increased survival, and younger age.
Children with tumors bearing IDH1 mutations were older than children
with mutation-negative tumors. The findings suggested that pediatric and
adult gliomas differ biologically.

In a retrospective study of 49 progressive astrocytomas, 42 (86%) of
which had somatic mutations in the IDH1 gene, Dubbink et al. (2009)
found that the presence of IDH1 mutations was significantly associated
with increased patient survival (median survival, 48 vs 98 months), but
did not affect outcome of treatment with temozolomide.

Bralten et al. (2011) found that overexpression of IDH1-R132H in
established glioma cell lines resulted in decreased proliferation and
more contact-dependent cell migration compared to wildtype.
Intracerebral injection of IDH1-R132H in mice, as compared to injection
of wildtype, resulted in increased survival and even absence of tumor in
1 mouse. Reduced cellular proliferation was associated with accumulation
of D-2-hydroxyglutarate that is produced by the R132H variant protein.
The decreased proliferation was not associated with increased apoptosis,
but was associated with decreased AKT1 (164730) activity. The findings
indicated that R132H dominantly reduces aggressiveness of established
glioma cell lines in vitro and in vivo. Bralten et al. (2011) noted that
the findings were apparently contradictory because the presence of an
IDH1 mutation was thought to contribute to tumorigenesis; the authors
suggested that IDH1 mutations may be involved in tumor initiation and
not in tumor progression. IDH1-mutant tumors are typically low-grade and
often slow-growing.

- Chromosome 7

In a series of human glioblastoma cell lines, Henn et al. (1986) found
that the most striking and consistent chromosomal finding was an
increase in copy number of chromosome 7. In all of the cell lines,
ERBB-specific mRNA (EGFR; 131550) was increased to levels even higher
than expected from the number of chromosomes 7 present. These changes
were not found in benign astrocytomas. Previously, Downward et al.
(1984) presented evidence that oncogene ERBB may be derived from the
gene coding for EGFR.

Bigner et al. (1988) determined that double minute chromosomes,
indicating the presence of gene amplification, are found in about 50% of
malignant gliomas. Most tumors with double minute chromosomes contain 1
of 5 amplified genes, most often the EGFR gene on chromosome 7.
Following up on the observation that the EGFR gene is amplified in 40%
of malignant gliomas, Wong et al. (1992) characterized the
rearrangements in 5 malignant gliomas. In one they found deletion of
most of the extracytoplasmic domain of the receptor. The 4 other tumors
had internal deletions of the gene.

Using array CGH, Pfister et al. (2008) found that 30 (45%) of 66
low-grade pediatric astrocytomas contained a somatic copy number gain at
chromosome 7q34 spanning the BRAF (164757) locus, among others. These
changes were associated with increased BRAF mRNA, and further studies
showed evidence for activation of the MAPK1 (176948) pathway and
downstream targets, such as ERK1/2 (see, e.g., 176872) and CCND1
(168461). Four (6%) of the tumors had an activating BRAF somatic
mutation (V600E; 164757.0001). Among 26 adult tumors, 16 (62%) had copy
number gains of the BRAF locus. Other changes in the 66 pediatric tumors
including large somatic trisomies of chromosomes 5 (6 of 66) and 7 (4 of
66). Initial in vitro pharmacologic studies suggested that inhibition of
the MAPK pathway may be possible.

Yu et al. (2009) found that 42 (60%) of 70 sporadic pilocytic
astrocytomas had rearrangements of the BRAF gene. Two additional tumors
with no rearrangement carried a BRAF mutation. Twenty-two of 36 tumors
with BRAF rearrangements had corresponding amplification of the
neighboring HIPK2 gene (606868). However, 14 of 36 tumors with BRAF
rearrangement had no detectable HIPK2 gene amplification. Six of 20
tumors demonstrated HIPK2 amplification without apparent BRAF
rearrangement or mutation. Only 12 (17%) of the 70 tumors lacked
detectable BRAF or HIPK2 alterations. Yu et al. (2009) concluded that
BRAF rearrangement represents the most common genetic alteration in
sporadic pilocytic astrocytomas.

- Chromosome 10

Bigner et al. (1988) concluded that the most frequent chromosomal
changes in malignant gliomas are gains of chromosome 7 and losses of
chromosome 10. Loss of 1 copy of chromosome 10 is a common event in
high-grade gliomas. Rearrangement and loss of at least some parts of the
second copy, especially in the 10q23-q26 region, has been demonstrated
in approximately 80% of glioblastoma multiforme tumors (Bigner and
Vogelstein, 1990).

Chromosome 10 was implicated in glioblastoma multiforme by Fujimoto et
al. (1989), who found loss of constitutional heterozygosity in tumor
samples from 10 of 13 patients in whom paired tumor and lymphocyte DNA
samples were screened. In a search for submicroscopic deletions in
chromosome 10, Fults and Pedone (1993) performed a RFLP analysis in 30
patients, using markers that had been mapped accurately on chromosome 10
by genetic linkage studies. Loss of heterozygosity (LOH) at one or more
loci was found in 15 of the 30 patients. In 7 cases, LOH was found at
every informative locus. LOH was confined to a portion of the long arm
in 6 patients; the smallest region of overlap among these 6 deletions
was flanked by markers D10S12 proximally and D10S6 distally, a 33.4-cM
region mapped physically near the telomere, 10q25.1-qter.

Karlbom et al. (1993) analyzed a panel of glial tumors consisting of 11
low-grade gliomas, 9 anaplastic gliomas, and 29 glioblastomas for loss
of heterozygosity by examining at least one locus for each chromosome.
The frequency of allele loss was highest among the glioblastomas,
suggesting that genetic alterations accumulate during glial tumor
development. The most common genetic alteration was found to involve
allele losses of chromosome 10 loci, these being found in all
glioblastomas and in 3 anaplastic tumors. Deletion mapping analysis
revealed partial loss of chromosome 10 in 8 glioblastomas and 2
anaplastic tumors in 3 distinct regions: one telomeric region on 1p and
both telomeric and centromeric locations on 10q. These data suggested to
Karlbom et al. (1993) the existence of multiple chromosome 10 tumor
suppressor gene loci whose inactivation is involved in the malignant
progression of glioma. In studies of 20 gliomas with microsatellite
markers from chromosome 10, the locus that exhibited the most loss (69%)
was the region bordered by D10S249 and D10S558 and inclusive of D10S594,
with a linkage distance of 3 cM (Kimmelman et al., 1996). This region
was known to be deleted in various grades of tumor, including low- and
high-grade tumors. Kimmelman et al. (1996) suggested that chromosome
region 10p15 is involved in human gliomas of diverse grades and that
this region may harbor genes important in the development of and
progression to the malignant phenotype.

See the DMBT1 gene (601969), so designated for 'deleted in malignant
brain tumors,' for a discussion of a gene on 10q25.3-q26.1 that showed
intragenic homozygous deletions in medulloblastoma and glioblastoma
multiforme tumor tissue and in brain tumor cell lines (Mollenhauer et
al., 1997). Chernova et al. (1998) isolated a novel gene on 10q24,
'leucine-rich gene, glioma-inactivated-1' (LGI1; 604619), which was
rearranged as a result of a t(10;19)(q24;q13) balanced translocation in
a glioblastoma cell line. See also the PTEN gene (601728) on 10q23.31 in
which Staal et al. (2002) identified a mutation in a patient with
oligodendroglioma (see GLM2, 613028).

Nishimoto et al. (2001) mapped a repressor of telomerase expression
(608045) to a 2.7-cM region on 10p15.1 by microcell-mediated chromosome
transfer (MMCT) into a telomerase-positive cell line. Loss of chromosome
10 is frequent in malignant gliomas. These data prompted Leuraud et al.
(2003) to investigate the specific relationship between telomerase
reactivation and LOH on 10p15.1 in high-grade gliomas. Leuraud et al.
(2003) analyzed a series of 51 high-grade gliomas for LOH on chromosome
10 and for telomerase activity. In univariate analysis, LOH on 10p,
found in 59% of the gliomas, and LOH of 10q, found in 61%, were
associated with telomerase activity. In the multivariate analysis, only
LOH10p remained statistically related to telomerase activity, suggesting
that the telomerase repressor gene located on 10p15.1 is inactivated in
high-grade gliomas.

- Chromosome 17p

El-Azouzi et al. (1989) described loss of constitutional heterozygosity
for markers on the short arm of chromosome 17 in both low-grade and
high-grade malignant astrocytomas, suggesting that this region may
contain a tumor suppressor gene associated with the early events in
tumorigenesis. Chattopadhyay et al. (1997) identified a locus at
17p13.3, independent of the p53 (191170) locus, as a genetic link in
glioma tumor progression. Jin et al. (2000) provided further evidence of
a glioma tumor suppressor gene distinct from p53 at 17p.

- Chromosomes 19 and 1

Bigner et al. (1988) found chromosome abnormalities in 12 of 54
malignant gliomas. Structural abnormalities of 9p (see GLM5, 613030) and
19q were increased to a statistically significant degree.

To evaluate whether loss of chromosome 19 alleles is common in glial
tumors of different types and grades, von Deimling et al. (1992)
performed Southern blot RFLP analysis for multiple chromosome 19 loci in
122 gliomas from 116 patients. In 29 tumors, loss of constitutional
heterozygosity of 19q was demonstrated; 4 tumors had partial deletion of
19q. The results were interpreted as indicating the presence of a glial
tumor suppressor gene on 19q.

Smith et al. (2000) generated a complete transcript map of a 150-kb
interval of chromosome 19q13.3, in which allelic loss is a frequent
event in human diffuse gliomas, and identified 2 novel transcripts,
designated GLTSCR1 (605690) and GLTSCR2 (605691). Mutation analysis of
the transcripts in this region in diffuse gliomas with 19q deletions
revealed no tumor-specific mutations.

Hoang-Xuan et al. (2001) examined the molecular profile of 26
oligodendrogliomas (10 WHO grade II and 16 WHO grade III) and found that
the most frequent alterations were loss of heterozygosity on 1p and 19q.
These 2 alterations were closely associated, suggesting that the 2 loci
are involved in the same pathway of tumorigenesis. Hoang-Xuan et al.
(2001) also found that the combination of homozygous deletion of the
P16/CDKN2A tumor suppressor gene, LOH on chromosome 10, and
amplification of the EGFR oncogene was present at a higher rate than
previously reported. A statistically significant exclusion was noted
between these 3 alterations and the LOH on 1p/19q, suggesting that there
are at least 2 distinct genetic subsets of oligodendroglioma. EGFR
amplification and LOH on 10q were significant predictors of shorter
progression-free survival (PFS), characterizing a more aggressive form
of tumor, whereas LOH on 1p was associated with longer PFS.

Ueki et al. (1997) studied gliomas for tumor-specific alterations in the
ANOVA gene (601991), which they cloned from the glioma candidate region
at 19q13.3. They found no alterations of ANOVA in gliomas by Southern
blot and SSCP analysis, suggesting that ANOVA is not the chromosome 19q
glioma tumor suppressor gene.

Labussiere et al. (2010) found that 315 (41%) of 764 gliomas had somatic
mutations in the IDH1 gene. All mutations were located at residue 132,
and nearly 90% resulted in an arg132-to-his (R132H) substitution.
Regarding 1p/19q status, 118 IDH1 mutations were found in the group of
tumors with a true 1p/19q deletion (118 of 128; 92%). In contrast, only
32% (51 of 159) of the tumors with a false 1p/19q signature harbored an
IDH1 mutation. Mutations in codon 172 of IDH2 were found in 16 (2.1%) of
the gliomas, and all 10 tumors with a true 1p/19q signature and no IDH1
mutation contained an IDH2 mutation. No tumor had mutations in both IDH1
and IDH2. Patients with IDH1 or IDH2 mutations had better survival than
those without these mutations, and those with IDH1 or IDH2 mutations and
with complete 1p/19q codeletion had longer survival than those with the
mutations alone. The findings indicated that IDH1/IDH2 mutation is a
constant feature in gliomas with complete 1p/19q codeletion, suggesting
a synergistic effect of these molecular changes.

Bettegowda et al. (2011) performed exonic sequencing of 7
oligodendrogliomas. Among other changes, they found that the CIC gene
(612082) (homolog of the Drosophila gene capicua) on chromosome 19q was
somatically mutated in 6 cases and that the FUBP1 (603444) gene on
chromosome 1p was somatically mutated in 2 tumors. Examination of 27
additional oligodendrogliomas revealed 12 and 3 more tumors with
mutations of CIC and FUBP1, respectively, 58% of which were predicted to
result in truncations of the encoded proteins. Bettegowda et al. (2011)
concluded that their results suggested a critical role for these genes
in the biology and pathology of oligodendrocytes.

- Chromosome 14q

Hu et al. (2002) performed allelotype analysis on 17 fibrillary
astrocytomas and 21 de novo glioblastoma multiforme and identified 2
common regions of deletions on 14q22.3-32.1 and 14q32.1-qter, suggesting
the presence of 2 putative tumor suppressor genes.

OTHER FEATURES

Cartron et al. (2002) examined the expression of BAX (600040) in 55
patients with glioblastoma multiforme. The authors identified a novel
form of BAX, designated BAX-psi, which was present in 24% of the
patients. BAX-psi is an N-terminal truncated form of BAX which results
from a partial deletion of exon 1 of the BAX gene. BAX-psi and the
wildtype form, BAX-alpha, are encoded by distinct mRNAs, both of which
are present in normal tissues. Glial tumors expressed either BAX-alpha
or BAX-psi proteins, an apparent consequence of an exclusive
transcription of the corresponding mRNAs. The BAX-psi protein was
preferentially localized to mitochondria and was a more powerful inducer
of apoptosis than BAX-alpha. BAX-psi tumors exhibited slower
proliferation in Swiss nude mice, and this feature could be circumvented
by the coexpression of the BCL2 (151430) transgene, the functional
antagonist of BAX. The expression of BAX-psi correlated with a longer
survival in patients (18 months versus 10 months for BAX-alpha
patients). The authors hypothesized a beneficial involvement of the psi
variant of BAX in tumor progression.

Esteller et al. (2000) analyzed the MGMT promoter (156569) in tumor DNA
by a methylation-specific PCR assay to determine whether methylation of
the MGMT promoter is related to the responsiveness of gliomas to
alkylating agents. The MGMT promoter was methylated in gliomas from 19
of 47 patients (40%). This finding was associated with regression of the
tumor and prolonged overall and disease-free survival. It was an
independent and stronger prognostic factor than age, stage, tumor grade,
or performance status. The authors concluded that methylation of the
MGMT promoter in gliomas is a useful predictor of the responsiveness of
the tumors to alkylating agents.

In an evaluation of combined radiotherapy and temozolomide for newly
diagnosed glioblastoma, Hegi et al. (2004) found that methylation of the
MGMT promoter in the tumor was associated with longer survival. Stupp et
al. (2005) showed that the addition of temozolomide to radiotherapy for
newly diagnosed glioblastoma resulted in a clinically meaningful and
statistically significant survival benefit with minimal additional
toxicity. Hegi et al. (2005) studied methylation of the MGMT promoter in
newly diagnosed glioblastomas and found that patients with a methylated
MGMT promoter in the glioblastoma benefited from temozolomide, whereas
those who did not have a methylated MGMT promoter did not have such a
benefit.

The epidermal growth factor receptor (EGFR; 131550) is frequently
amplified, overexpressed, or mutated in glioblastomas, but only 10 to
20% of patients have a response to EGFR kinase inhibitors. In studies
designed to demonstrate molecular determinants of response, Mellinghoff
et al. (2005) reviewed the findings of 49 patients with recurrent
malignant glioma treated with EGFR kinase inhibitors. Tumor shrinkage of
at least 25% occurred in 9 patients. Pretreatment tissue was available
for molecular analysis from 26 patients, 7 of whom had had a response
and 19 of whom had rapid progression during therapy. No mutations in
EGFR or Her2/neu (164870) kinase domains were detected in the tumors.
Glioblastomas often express EGFRvIII, a constitutively active genomic
deletion variant of EGFR (Aldape et al., 2004; Frederick et al., 2000).
Mellinghoff et al. (2005) found that coexpression of EGFRvIII and PTEN
(601728) was significantly associated with clinical response to EGFR
kinase inhibitors. Furthermore, they found that in vitro, coexpression
of EGFRvIII and PTEN sensitized glioblastoma cells to the kinase
inhibitor erlotinib.

Muller et al. (2012) proposed that homozygous deletions in passenger
genes in cancer deletions can expose cancer-specific therapeutic
vulnerabilities when the collaterally deleted gene is a member of a
functionally redundant family of genes carrying out an essential
function. The glycolytic gene enolase-1 (ENO1; 172430) in the 1p36 locus
is deleted in glioblastoma, which is tolerated by the expression of ENO2
(131360). Muller et al. (2012) showed that short hairpin RNA-mediated
silencing of ENO2 selectively inhibits growth, survival, and the
tumorigenic potential of ENO1-deleted GBM cells, and that the enolase
inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted
GBM cells relative to ENO1-intact GBM cells or normal astrocytes. Muller
et al. (2012) suggested that the principle of collateral vulnerability
should be applicable to other passenger-deleted genes encoding
functionally redundant essential activities and provide an effective
treatment strategy for cancers containing such genomic events.

ANIMAL MODEL

Holland et al. (2000) transferred, in a tissue-specific manner, genes
encoding activated forms of Ras (190070) and Akt (164730) to astrocytes
and neural progenitors in mice. They found that although neither
activated Ras nor Akt alone was sufficient to induce glioblastoma
multiforme formation, the combination of activated Ras and Akt induced
high-grade gliomas with the histologic features of human GBMs. These
tumors appeared to arise after gene transfer to neural progenitors, but
not after transfer to differentiated astrocytes. Increased activity of
RAS is found in many human GBMs, and Holland et al. (2000) demonstrated
that AKT activity is increased in most of these tumors, implying that
combined activation of these 2 pathways accurately models the biology of
this disease.

Gutmann et al. (2002) generated a transgenic mouse model that targeted
an activated Ras molecule to astrocytes, resulting in high-grade
astrocytoma development in 3 to 4 months. They used high-density
oligonucleotide arrays to perform gene expression profiling on cultured
wildtype mouse astrocytes, non-neoplastic transgenic astrocytes, and
neoplastic astrocytes. The authors identified changes in different
groups of genes, including those associated with cell adhesion and
cytoskeleton-mediated processes, astroglial-specific genes, growth
regulation and, in particular, a reduced expression of GAP43 (162060),
suggesting that it regulates growth in astrocytes.

Reilly et al. (2000) studied a mutant mouse model of astrocytoma (NPcis)
in which both the Nf1 (613113) and Trp53 (191170) genes are mutated and
are so tightly linked on chromosome 11 that they are inherited as a
single mutation in genetic crosses. The mice on a C57BL/6J(B6) inbred
strain background developed astrocytomas spontaneously, progressing to
glioblastoma. Reilly et al. (2004) presented data that mice mutant for
the 2 genes on a 129S4/SvJae background are highly resistant to
developing astrocytomas. Through analysis of F1 progeny, they
demonstrated that susceptibility to astrocytoma is linked to mouse
chromosome 11 and that the modifier gene(s) responsible for differences
in susceptibility is closely linked to Nf1 and Trp53. Furthermore, this
modifier of astrocytoma susceptibility was itself epigenetically
modified. These data demonstrated that epigenetic effects can have a
strong effect on whether cancer develops in the context of mutant ras
signaling and mutant p53. Reilly et al. (2004) suggested that this mouse
model of astrocytoma can be used to identify modifier phenotypes with
complex inheritance patterns that would be unidentifiable in humans.

Zheng et al. (2008) showed that concomitant central nervous system
(CNS)-specific deletion of p53 and Pten (601728) in the mouse CNS
generates a penetrant acute-onset high grade malignant glioma phenotype
with notable clinical, pathologic, and molecular resemblance to primary
glioblastoma in humans. This genetic observation prompted TP53 and PTEN
mutational analysis in human primary glioblastoma, demonstrating
unexpectedly frequent inactivating mutations of TP53 as well as the
expected PTEN mutations. Integrated transcriptomic profiling, in silico
promoter analysis, and functional studies of murine neural stem cells
established that dual, but not singular, inactivation of p53 and Pten
promotes an undifferentiated state with high renewal potential and
drives increased Myc protein levels and its associated signature.
Functional studies validated increased Myc activity as a potent
contributor to the impaired differentiation and enhanced renewal of
neural stem cells doubly null for p53 and Pten (p53-/-Pten-/-) as well
as tumor neurospheres derived from this model. Myc also serves to
maintain robust tumorigenic potential of p53-/-Pten-/- tumor
neurospheres. These murine modeling studies, together with confirmatory
transcriptomic/promoter studies in human primary glioblastoma, validated
a pathogenetic role of a common tumor suppressor mutation profile in
human primary glioblastoma and established Myc as an important target
for cooperative actions of p53 and Pten in the regulation of normal and
malignant stem/progenitor cell differentiation, self-renewal, and
tumorigenic potential.

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Olopade et al. (1992); Parkinson and Hall (1962); Reese et al. (1944);
Simons et al. (1999); Von Motz et al. (1977)
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Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G. J.;
Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K.
W.; Velculescu, V. E.; Vogelstein, B.; Bigner, D. D.: IDH1 and IDH2
mutations in gliomas. New Eng. J. Med. 360: 765-773, 2009.

105. Yokota, T.; Tachizawa, T.; Fukino, K.; Teramoto, A.; Kouno, J.;
Matsumoto, K.; Emi, M.: A family with spinal anaplastic ependymoma:
evidence of loss of chromosome 22q in tumor. J. Hum. Genet. 48:
598-602, 2003.

106. Yu, J.; Deshmukh, H.; Gutmann, R. J.; Emnett, R. J.; Rodriguez,
F. J.; Watson, M. A.; Nagarajan, R.; Gutmann, D. H.: Alterations
of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73:
1526-1531, 2009.

107. Zheng, H.; Ying, H.; Yan, H.; Kimmelman, A. C.; Hiller, D. J.;
Chen, A.-J.; Perry, S. R.; Tonon, G.; Chu, G. C.; Ding, Z.; Stommel,
J. M.; Dunn, K. L.; Wiedemeyer, R.; You, M. J.; Brennan, C.; Wang,
Y. A.; Ligon, K. L.; Wong, W. H.; Chin, L.; DePinho, R. A.: p53 and
Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature 455:
1129-1133, 2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant;
Somatic mutation

NEOPLASIA:
Astrocytomas;
Glioblastoma multiforme;
Oligodendrogliomas;
Ependymomas;
Subependymomas

MISCELLANEOUS:
Gliomas may occur in association with other hereditary tumor syndromes
(see 276300, 155755, 162200, 101000, 191100)

MOLECULAR BASIS:
Susceptibility conferred by mutation in the tumor protein p53 gene
(TP53, 191170.0042)

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 01/14/2013

*FIELD* CN
Ada Hamosh - updated: 01/28/2014
Ada Hamosh - updated: 6/24/2013
Cassandra L. Kniffin - updated: 3/4/2013
Cassandra L. Kniffin - updated: 12/11/2012
Ada Hamosh - updated: 10/31/2012
Ada Hamosh - updated: 9/12/2012
Ada Hamosh - updated: 6/19/2012
Ada Hamosh - updated: 3/13/2012
Ada Hamosh - updated: 3/7/2012
Ada Hamosh - updated: 11/22/2011
Cassandra L. Kniffin - updated: 6/21/2011
Cassandra L. Kniffin - updated: 4/14/2011
Cassandra L. Kniffin - updated: 1/24/2011
Cassandra L. Kniffin - updated: 9/30/2010
Cassandra L. Kniffin - updated: 6/25/2010
Ada Hamosh - updated: 2/18/2010
Anne M. Stumpf - reorganized: 9/25/2009
Ada Hamosh - updated: 9/16/2009
Cassandra L. Kniffin - updated: 6/10/2009
Cassandra L. Kniffin - updated: 4/10/2009
Cassandra L. Kniffin - updated: 3/19/2009
Ada Hamosh - updated: 3/12/2009
Ada Hamosh - updated: 11/26/2008
Ada Hamosh - updated: 10/20/2008
Cassandra L. Kniffin - updated: 6/18/2008
Ada Hamosh - updated: 1/23/2007
Victor A. McKusick - updated: 12/5/2005
Victor A. McKusick - updated: 3/28/2005
Marla J. F. O'Neill - updated: 3/17/2005
Victor A. McKusick - updated: 2/22/2005
Victor A. McKusick - updated: 8/15/2003
Cassandra L. Kniffin - updated: 12/6/2002
Cassandra L. Kniffin - updated: 11/13/2002
George E. Tiller - updated: 10/17/2002
Cassandra L. Kniffin - reorganized: 9/26/2002
Cassandra L. Kniffin - updated: 9/26/2002
Victor A. McKusick - updated: 8/23/2002
Cassandra L. Kniffin - updated: 5/29/2002
Victor A. McKusick - updated: 2/28/2002
Michael J. Wright - updated: 7/23/2001
Sonja A. Rasmussen - updated: 10/12/2000
Ada Hamosh - updated: 4/28/2000
Victor A. McKusick - updated: 1/19/2000
Orest Hurko - updated: 4/6/1998
Victor A. McKusick - updated: 9/12/1997
Victor A. McKusick - updated: 9/2/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
alopez: 01/28/2014
mcolton: 11/26/2013
carol: 7/10/2013
alopez: 6/24/2013
terry: 4/4/2013
alopez: 3/8/2013
carol: 3/7/2013
ckniffin: 3/4/2013
carol: 1/9/2013
terry: 12/20/2012
carol: 12/11/2012
ckniffin: 12/11/2012
alopez: 11/5/2012
terry: 10/31/2012
alopez: 9/13/2012
terry: 9/12/2012
alopez: 6/26/2012
terry: 6/19/2012
carol: 4/11/2012
alopez: 3/13/2012
alopez: 3/12/2012
terry: 3/7/2012
terry: 1/17/2012
alopez: 11/29/2011
terry: 11/22/2011
wwang: 7/6/2011
ckniffin: 6/21/2011
terry: 6/21/2011
carol: 6/17/2011
wwang: 4/25/2011
ckniffin: 4/14/2011
wwang: 2/17/2011
ckniffin: 1/24/2011
mgross: 10/22/2010
wwang: 10/8/2010
ckniffin: 9/30/2010
wwang: 7/7/2010
ckniffin: 6/25/2010
carol: 5/20/2010
terry: 5/20/2010
alopez: 2/22/2010
carol: 2/18/2010
terry: 2/18/2010
ckniffin: 1/15/2010
terry: 12/16/2009
carol: 11/23/2009
alopez: 10/5/2009
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alopez: 9/25/2009
terry: 9/16/2009
wwang: 6/12/2009
ckniffin: 6/10/2009
wwang: 4/29/2009
ckniffin: 4/10/2009
wwang: 4/10/2009
ckniffin: 3/19/2009
alopez: 3/18/2009
terry: 3/12/2009
terry: 2/3/2009
alopez: 12/9/2008
terry: 11/26/2008
alopez: 10/22/2008
terry: 10/20/2008
alopez: 6/27/2008
ckniffin: 6/18/2008
wwang: 5/19/2008
ckniffin: 5/15/2008
carol: 4/4/2008
alopez: 1/24/2007
terry: 1/23/2007
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wwang: 3/28/2005
wwang: 3/17/2005
wwang: 3/9/2005
terry: 2/22/2005
cwells: 11/10/2003
alopez: 9/30/2003
alopez: 8/18/2003
terry: 8/15/2003
carol: 5/16/2003
cwells: 12/9/2002
ckniffin: 12/6/2002
tkritzer: 12/2/2002
cwells: 11/26/2002
ckniffin: 11/13/2002
cwells: 10/17/2002
ckniffin: 10/3/2002
carol: 9/26/2002
ckniffin: 9/20/2002
mgross: 8/23/2002
carol: 6/3/2002
ckniffin: 5/29/2002
cwells: 5/29/2002
cwells: 3/1/2002
terry: 2/28/2002
alopez: 7/27/2001
terry: 7/23/2001
terry: 6/4/2001
mcapotos: 10/13/2000
mcapotos: 10/12/2000
alopez: 5/1/2000
terry: 4/28/2000
mcapotos: 1/21/2000
terry: 1/19/2000
carol: 12/17/1998
carol: 6/22/1998
terry: 4/6/1998
terry: 9/12/1997
jenny: 9/3/1997
terry: 9/2/1997
mark: 2/18/1997
terry: 2/6/1997
terry: 6/26/1996
terry: 6/21/1996
mark: 3/26/1996
terry: 3/21/1996
mark: 5/15/1995
mimadm: 9/24/1994
terry: 4/27/1994
pfoster: 2/18/1994
carol: 11/12/1993
carol: 10/29/1993

MIM 147700
*RECORD*
*FIELD* NO
147700
*FIELD* TI
*147700 ISOCITRATE DEHYDROGENASE 1; IDH1
;;ISOCITRATE DEHYDROGENASE, NADP(+)-SPECIFIC, SOLUBLE;;
read morePEROXISOMAL ISOCITRATE DEHYDROGENASE; PICD;;
ISOCITRATE DEHYDROGENASE, NADP(+)-DEPENDENT, CYTOSOLIC; IDPC; ICDC
*FIELD* TX

DESCRIPTION

IDH1 is a dimeric cytosolic NADP-dependent isocitrate dehydrogenase (EC
1.1.1.42) that catalyzes decarboxylation of isocitrate into
alpha-ketoglutarate (Nekrutenko et al., 1998).

CLONING

By RT-PCR of placenta RNA, followed by PCR of an adult liver cDNA
library, Nekrutenko et al. (1998) cloned human IDH1. The deduced
414-amino acid protein has a calculated molecular mass of 46.7 kD. It
contains a dehydrogenase and isopropylmalate dehydrogenase signature
sequence, 7 conserved residues predicted to be involved in isocitrate
binding, and a C-terminal peroxisomal-targeting signal. Human IDH1
shares about 95% amino acid identity with Idh1 from mouse and 2 species
of vole.

By searching databases for sequences similar to S. cerevisiae Idp3,
Geisbrecht and Gould (1999) identified a human colon carcinoma cDNA
encoding IDH1, which they called PICD. The deduced protein shares 59%
identity with yeast Idp3. Western blot analysis of a human
hepatocellular carcinoma cell line detected PICD at an apparent
molecular mass of 46 kD. In fractionated cells, most PICD associated
with the cytosolic fraction, although a significant amount colocalized
with a peroxisomal marker. In rat liver cells, about 27% of total Picd
protein was associated with peroxisomes.

GENE FUNCTION

Geisbrecht and Gould (1999) found that purified recombinant human PICD
catalyzed oxidative decarboxylation of isocitric acid and required NADP+
for the reaction. In addition, human PICD could complement the oleate
growth defect in Idp3-null yeast.

Shechter et al. (2003) found that expression of IDH1 mRNA increased
2.3-fold and IDH1 activity increased 63% in sterol-deprived HepG2 cells.
The IDH1 promoter region was activated by expression of SREBP1A (SREBF1;
184756) and, to a lesser degree, SREBP2 (SREBF2; 600481).
Electrophoretic mobility shift assays confirmed preferential binding of
SREBP1A to an SREBP-binding element located at nucleotides -44 to -25 in
the IDH1 promoter region. Shechter et al. (2003) concluded that IDH1
activity is coordinately regulated with the cholesterol and fatty acid
biosynthetic pathways, suggesting that IDH1 provides the cytosolic NADPH
required by these pathways.

Using 2-dimensional PAGE and Western blot analysis, Memon et al. (2005)
found that expression of IDPC was downregulated in a poorly
differentiated bladder cancer cell line compared with a
well-differentiated bladder cancer cell line. Tissue biopsies of
late-stage bladder cancers also showed IDPC downregulation compared with
early-stage bladder cancers.

Ronnebaum et al. (2006) found that downregulation of Icdc via small
interfering RNA impaired glucose-stimulated insulin secretion in 2 rat
insulinoma cell lines and in primary rat islets. Suppression of Icdc
also attenuated the glucose-induced increments in pyruvate cycling
activity and in NADPH levels, as well as total cellular NADP(H) content.
Metabolic profiling of 8 organic acids in cell extracts revealed that
suppression of Icdc increased lactate production, consistent with
attenuation of pyruvate cycling, with no significant changes in other
intermediates. Ronnebaum et al. (2006) concluded that ICDC plays an
important role in the control of glucose-stimulated insulin secretion.

Metallo et al. (2012) showed that human cells use reductive metabolism
of alpha-ketoglutarate to synthesize acetyl-coenzyme A (AcCoA) for lipid
synthesis. This IDH1-dependent pathway is active in most cell lines
under normal culture conditions, but cells grown under hypoxia rely
almost exclusively on the reductive carboxylation of glutamine-derived
alpha-ketoglutarate for de novo lipogenesis. Furthermore, renal cell
lines deficient in the von Hippel-Lindau tumor suppressor protein (VHL;
608537) preferentially use reductive glutamine metabolism for lipid
biosynthesis even at normal oxygen levels. Metallo et al. (2012)
concluded that their results identified a critical role for oxygen in
regulating carbon use to produce AcCoA and support lipid synthesis in
mammalian cells.

Mullen et al. (2012) showed that tumor cells with defective mitochondria
use glutamine-dependent reductive carboxylation rather than oxidative
metabolism as the major pathway of citrate formation. This pathway uses
mitochondrial and cytosolic isoforms of NADP+/NADPH-dependent IDH1, and
subsequent metabolism of glutamine-derived citrate provides both the
AcCoA for lipid synthesis and the 4-carbon intermediates needed to
produce the remaining citric acid cycle (CAC) metabolites and related
macromolecular precursors. This reductive, glutamine-dependent pathway
is the dominant mode of metabolism in rapidly growing malignant cells
containing mutations in complex I or complex III of the electron
transport chain (ECT), in patient-derived renal carcinoma cells with
mutations in fumarate hydratase (136850), and in cells with normal
mitochondria subjected to acute pharmacologic ECT inhibition. Mullen et
al. (2012) concluded that their findings revealed the novel induction of
a versatile glutamine-dependent pathway that reverses many of the
reactions of the canonical CAC, supports tumor cell growth, and explains
how cells generate pools of CAC intermediates in the face of impaired
mitochondrial metabolism.

Lu et al. (2012) reported that 2-hydroxyglutarate (2HG)-producing IDH
mutants can prevent the histone demethylation that is required for
lineage-specific progenitor cells to differentiate into terminally
differentiated cells. In tumor samples from glioma patients, IDH
mutations were associated with a distinct gene expression profile
enriched for genes expressed in neural progenitor cells, and this was
associated with increased histone methylation. To test whether the
ability of IDH mutants to promote histone methylation contributes to a
block in cell differentiation in nontransformed cells, Lu et al. (2012)
tested the effect of neomorphic IDH mutants on adipocyte differentiation
in vitro. Introduction of either mutant IDH or cell-permeable 2HG was
associated with repression of the inducible expression of
lineage-specific differentiation genes and a block to differentiation.
This correlated with a significant increase in repressive histone
methylation marks without observable changes in promoter DNA
methylation. Gliomas were found to have elevated levels of similar
histone repressive marks. Stable transfection of a 2HG-producing mutant
IDH into immortalized astrocytes resulted in progressive accumulation of
histone methylation. Of the marks examined, increased H3K9 methylation
reproducibly preceded a rise in DNA methylation as cells were passaged
in culture. Furthermore, Lu et al. (2012) found that the 2HG-inhibitable
H3K9 demethylase KDM4C (605469) was induced during adipocyte
differentiation, and that RNA-interference suppression of KDM4C was
sufficient to block differentiation. Lu et al. (2012) concluded that,
taken together, their data demonstrated that 2HG can inhibit histone
demethylation and that inhibition of histone demethylation can be
sufficient to block the differentiation of nontransformed cells.

Turcan et al. (2012) showed that mutation of IDH1 establishes the glioma
CpG island methylator (G-CIMP) phenotype by remodeling the methylome.
This remodeling results in reorganization of the methylome and
transcriptome. Examination of the epigenome of a large set of
intermediate-grade gliomas demonstrated a distinct G-CIMP phenotype that
is highly dependent on the presence of IDH mutation. Introduction of
mutant IDH1 into primary human astrocytes altered specific histone
marks, induced extensive DNA hypermethylation, and reshaped the
methylome in a fashion that mirrored the changes observed in
G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic
alterations resulting from mutant IDH1 activated key gene expression
programs, characterized G-CIMP-positive proneural glioblastomas but not
other glioblastomas, and were predictive of improved survival. Turcan et
al. (2012) concluded that their findings demonstrated that IDH mutation
is the molecular basis of CIMP in gliomas, provided a framework for
understanding oncogenesis in these gliomas, and highlighted the
interplay between genomic and epigenomic changes in human cancers.

Koivunen et al. (2012) showed that the R-enantiomer of 2HG (R-2HG),
produced by cancer-associated mutant IDH1 or IDH2, but not S-2HG,
stimulates EGLN (e.g., EGLN1; 606425) activity, leading to diminished
HIF (see 603348) levels, which enhances the proliferation and soft agar
growth of human astrocytes. Koivunen et al. (2012) concluded that their
findings defined an enantiomer-specific mechanism by which the R-2HG
that accumulates in IDH mutant brain tumors promotes transformation.

BIOCHEMICAL FEATURES

Xu et al. (2004) performed structural studies of human IDH1 in complex
with NADP and with NADP, isocitrate, and Ca(2+) and identified 3
conformational states of the enzyme. A structural segment at the active
site assumed a loop conformation in the open, inactive state, a
partially unraveled alpha helix in the semi-open, intermediate state,
and an alpha helix in the closed, active state. In the active
conformation, asp279 formed a hydrogen bond with Ca(2+) to participate
in the catalytic reaction. In the inactive conformation, asp279 formed a
hydrogen bond with ser94 and hindered access of isocitrate to the active
site. Since serine phosphorylation inactivates E. coli Idh, Xu et al.
(2004) proposed that the hydrogen bond formed between asp279 and ser94
may mimic an inactivating serine phosphorylation.

GENE STRUCTURE

Shechter et al. (2003) determined that the IDH1 gene contains 10 exons
and spans 18.9 kb. The first 2 exons are untranslated and contain 5
putative transcription start sites. Nucleotides -44 to -25 contain an
SREBP-binding element (GTGGGCTGAG).

MAPPING

Chen et al. (1972) found rare variants of soluble IDH and concluded that
the structural gene is probably autosomal and that it is distinct from
the locus governing the mitochondrial form. Shows (1972) presented cell
hybridization data suggesting that soluble malate dehydrogenase (MDH1;
154200) and IDH are syntenic. Using the cell-hybrid method which relies
on interspecies variation rather than polymorphism, Boone et al. (1972)
concluded that the IDH locus is on chromosome 20. The assignment of
soluble IDH and soluble MDH to chromosome 20 was withdrawn (Ruddle,
1973). Creagan et al. (1974) presented evidence that these 2 syntenic
loci are on chromosome 2. From study of a balanced reciprocal
translocation (X;2)(p22;q32) in man-mouse hybrids, Van Cong (1976)
concluded that IDH1 is located in the region 2q32-qter. By dosage effect
in cases of chromosome 2 aberrations, Narahara et al. (1985) concluded
that the IDH1 locus is on chromosome 2q33.3, probably in the proximal
portion.

MOLECULAR GENETICS

- Role in Gliomas

To identify the genetic alterations in glioblastoma multiforme (GBM; see
137800), Parsons et al. (2008) sequenced 20,661 protein-coding genes,
determined the presence of amplifications and deletions using
high-density oligonucleotide arrays, and performed gene expression
analyses using next-generation sequencing technologies in 22 human tumor
samples. This comprehensive analysis led to the discovery of a variety
of genes that were not known to be altered in GBMs. Most notably,
Parsons et al. (2008) found recurrent mutations in the active site of
IDH1 in 12% of GBM patients. Mutations in IDH1 occurred in a large
fraction of young patients and in most patients with secondary GBMs and
were associated with an increase in overall survival. Parsons et al.
(2008) concluded that their studies demonstrated the value of unbiased
genomic analyses in the characterization of human brain cancer and
identified a potentially useful genetic alteration for the
classification and targeted therapy of GBMs. Parsons et al. (2008) found
that the hazard ratio for death among 79 patients with wildtype IDH1, as
compared to 11 with mutant IDH1, was 3.7 (95% confidence interval, 2.1
to 6.5; p less than 0.001). The median survival was 3.8 years for
patients with mutated IDH1, as compared to 1.1 years for patients with
wildtype IDH1. Parsons et al. (2008) found that a majority of tumors
analyzed had alterations in genes encoding components of each of the
TP53 (191170), RB1 (614041), and PI3K (see 171834) pathways.

Yan et al. (2009) determined the sequence of the IDH1 gene and related
IDH2 (147650) gene in 445 central nervous system (CNS) tumors and 494
non-CNS tumors. The enzymatic activity of the proteins that were
produced from normal and mutant IDH1 and IDH2 genes was determined in
cultured glioma cells that were transfected with these genes. Yan et al.
(2009) identified mutations that affected amino acid 132 of IDH1 in more
than 70% of World Health Organization (WHO) grade II and III
astrocytomas and oligodendrogliomas and in glioblastomas that developed
from these lower-grade lesions. Tumors without mutations in IDH1 often
had mutations affecting the analogous amino acid (R172) of the IDH2
gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and
clinical characteristics, and patients with such tumors had a better
outcome than those with wildtype IDH genes. Each of the 4 tested IDH1
and IDH2 mutations reduced the enzymatic activity of the encoded
protein. Yan et al. (2009) concluded that mutations of NADP(+)-dependent
isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority
of several types of malignant gliomas.

Zhao et al. (2009) showed that mutation to arginine of codon 132 of IDH1
impairs the enzyme's affinity for its substrate and dominantly inhibits
wildtype IDH1 activity through the formation of catalytically inactive
heterodimers. Forced expression of mutant IDH1 in cultured cells reduced
formation of the enzyme product, alpha ketoglutarate (alpha-KG), and
increased the levels of hypoxia-inducible factor subunit HIF1-alpha
(603348), a transcription factor that facilitates tumor growth when
oxygen is low and whose stability is regulated by alpha-KG. The rise in
HIF1-alpha levels was reversible by an alpha-KG derivative. HIF1-alpha
levels were higher in human gliomas harboring an IDH1 mutation than in
tumors without a mutation. Thus, Zhao et al. (2009) concluded that IDH1
appears to function as a tumor suppressor that, when mutationally
inactivated, contributes to tumorigenesis in part through induction of
the HIF1 pathway.

Dang et al. (2009) showed that cancer-associated IDH1 mutations result
in a new ability of the enzyme to catalyze the NADPH-dependent reduction
of alpha-ketoglutarate to D-2-hydroxyglutarate (2HG). Structural studies
demonstrated that when arg132 is mutated to his (R132H), residues in the
active site are shifted to produce structural changes consistent with
reduced oxidative decarboxylation of isocitrate and acquisition of the
ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of
2HG has been shown to lead to an elevated risk of malignant brain tumors
in patients with inborn errors of 2HG metabolism (Aghili et al., 2009)
(see 600721). Similarly, in human malignant gliomas harboring IDH1
mutations, Dang et al. (2009) found markedly elevated levels of 2HG.
Dang et al. (2009) concluded that their data demonstrated that the IDH1
mutations result in production of the oncometabolite 2HG, and indicated
that the excess 2HG which accumulates in vivo contributes to the
formation and malignant progression of gliomas.

In a retrospective study of 49 progressive astrocytomas, 42 (86%) of
which had somatic mutations in the IDH1 gene, Dubbink et al. (2009)
found that the presence of IDH1 mutations was significantly associated
with increased patient survival (median survival, 48 vs 98 months), but
did not affect outcome of treatment with temozolomide.

Bralten et al. (2011) found that overexpression of IDH1-R132H in
established glioma cell lines resulted in decreased proliferation and
more contact-dependent cell migration compared to wildtype.
Intracerebral injection of IDH1-R132H in mice, as compared to injection
of wildtype IDH1, resulted in increased survival and even absence of
tumor in 1 mouse. Reduced cellular proliferation was associated with
accumulation of D-2-hydroxyglutarate that is produced by the R132H
variant protein. The decreased proliferation was not associated with
increased apoptosis, but was associated with decreased AKT1 (164730)
activity. The findings indicated that R132H dominantly reduces
aggressiveness of established glioma cell lines in vitro and in vivo.
Bralten et al. (2011) noted that the findings were apparently
contradictory because the presence of an IDH1 mutation was thought to
contribute to tumorigenesis. The authors suggested that IDH1 mutations
may be involved in tumor initiation and not in tumor progression.

- Role in Acute Myeloid Leukemia

Mardis et al. (2009) identified the R132C mutation in 8 of 188 acute
myeloid leukemia (AML; 601626) samples and the R132H mutation in 7 of
188 samples. The R132S mutation was seen in 1 sample. Mutation of the
IDH1 gene was strongly correlated with a normal cytogenetic status; it
was present in 13 of 80 cytogenetically normal samples (16%).

Schnittger et al. (2010) identified somatic heterozygous mutations in
the IDH1 gene in samples from 93 (6.6%) of 1,414 patients with AML. Five
different mutations at codon arg132 were observed, with R132C being the
most common (54.8%). Patients with IDH1 mutations more commonly had an
immature immunophenotype (p less than 0.001), were female (p = 0.003),
had shorter overall survival (p = 0.110), a shorter event-free survival
(p less than 0.003), and a higher cumulative risk for relapse (p =
0.001). More than 73% of all IDH1-mutated cases had additional molecular
defects, most frequently in NPM1 (164040), compatible with a
multiple-hit hypothesis of AML pathogenesis. The data indicated that
IDH1 status may add information regarding characterization and
prognostication in AML.

Losman et al. (2013) found that expression of the canonical IDH1 mutant
R132H in human erythroleukemia cells and immortalized
granulocyte-macrophage progenitor cells promoted growth factor
independence and impaired differentiation, 2 hallmarks of leukemic
transformation. These effects could be recapitulated by
(R)-2-hydroxyglutarate, but not (S)-2-hydroxyglutarate, despite the fact
that (S)-2-hydroxyglutarate more potently inhibits enzymes, such as the
5-prime-methylcytosine TET2 (300255), that had been linked to the
pathogenesis of IDH mutant tumors. Losman et al. (2013) provided
evidence that this paradox relates to the ability of
(S)-2-hydroxyglutarate but not not (R)-2-hydroxyglutarate to inhibit the
EglN (606425) prolyl hydroxylases. Additionally, Losman et al. (2013)
showed that transformation by (R)-2-hydroxyglutarate is reversible.

The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. The Cancer Genome Atlas Research Network (2013) identified
recurrent mutations in the IDH1 or IDH2 (147650) genes in 39/200 (20%)
samples.

Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that IDH1 was among several genes in their study
whose mutations were often found in subclones, suggesting that they are
often cooperating mutations. The authors also identified other genes
that contained mutations they considered probable initiators.

- Role in Multiple Endochondromatosis

For a discussion of somatic IDH1 and IDH2 mutations in multiple
endochondromatosis, see Ollier disease (166000) and Maffucci syndrome
(614569).

ANIMAL MODEL

Sasaki et al. (2012) reported the characterization of conditional
knockin mice in which the most common IDH1 mutation, R132H, is inserted
into the endogenous murine Idh1 locus and is expressed in all
hematopoietic cells or specifically in cells of the myeloid lineage.
These mutants showed increased numbers of early hematopoietic
progenitors and developed splenomegaly and anemia with extramedullary
hematopoiesis, suggesting a dysfunctional bone marrow niche.
Furthermore, the myeloid-specific knockin cells had hypermethylated
histones and changes to DNA methylation similar to those observed in
human IDH1- or IDH2-mutant AML. Sasaki et al. (2012) concluded that, to
their knowledge, theirs was the first study to describe the generation
and characterization of conditional IDH1(R132H)-knockin mice, and also
the first to report the induction of a leukemic DNA methylation
signature in a mouse model.

*FIELD* SA
Henderson (1968); Henderson (1965); Turner et al. (1974); Weil et
al. (1977)
*FIELD* RF
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*FIELD* CN
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 4/12/2013
Cassandra L. Kniffin - updated: 3/4/2013
Ada Hamosh - updated: 9/18/2012
Ada Hamosh - updated: 7/17/2012
Nara Sobreira - updated: 5/25/2012
Ada Hamosh - updated: 2/8/2012
Cassandra L. Kniffin - updated: 8/2/2011
Cassandra L. Kniffin - updated: 1/24/2011
Ada Hamosh - updated: 7/1/2010
Ada Hamosh - updated: 1/8/2010
Ada Hamosh - updated: 9/15/2009
Ada Hamosh - updated: 6/16/2009
Ada Hamosh - updated: 3/12/2009
Ada Hamosh - updated: 10/20/2008
Patricia A. Hartz - updated: 9/12/2008

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 4/12/2013
carol: 3/7/2013
ckniffin: 3/4/2013
alopez: 9/19/2012
terry: 9/18/2012
alopez: 7/19/2012
terry: 7/17/2012
carol: 5/25/2012
alopez: 2/13/2012
terry: 2/8/2012
wwang: 8/10/2011
ckniffin: 8/2/2011
carol: 6/17/2011
wwang: 2/17/2011
ckniffin: 1/24/2011
terry: 7/1/2010
alopez: 1/11/2010
terry: 1/8/2010
alopez: 9/16/2009
terry: 9/15/2009
alopez: 6/23/2009
terry: 6/16/2009
alopez: 3/18/2009
terry: 3/12/2009
alopez: 10/23/2008
alopez: 10/22/2008
terry: 10/20/2008
mgross: 9/19/2008
mgross: 9/18/2008
terry: 9/12/2008
psherman: 2/9/2000
alopez: 9/5/1997
mark: 3/25/1996
mimadm: 4/14/1994
warfield: 4/12/1994
supermim: 3/16/1992
carol: 1/31/1991
supermim: 3/20/1990
supermim: 3/6/1990