10.1007/s00401-008-0455-2</TITLE= > <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18372"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Acta Neuropathologica</TD></TR> <TR> <TD>=A9 Springer-Verlag 2008</TD></TR> <TR> <TD>10.1007/s00401-008-0455-2</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Original Paper</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Analysis of the IDH1 = codon 132=20 mutation in brain tumors </DIV> J=F6rg Balss1, = Jochen Meyer1,=20 Wolf Mueller2, Andrey Korshunov2, 1,=20 Christian Hartmann2, 1 and = Andreas von Deimling2,=20 1 <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#ContactOfAuthor6"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/r027823071548868/contact.gif">= </A> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff2></A>(1) </TD> <TD>Clinical Cooperation Unit = Neuropathology G380,=20 German Cancer Research Center, 69120 Heidelberg,=20 Germany</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff1></A>(2) </TD> <TD>Department of Neuropathology, = Institute of=20 Pathology, Ruprecht-Karls-Universit=E4t Heidelberg, Im Neuenheimer = Feld=20 220/221, 69120 Heidelberg, = Germany</TD></TR></TBODY></TABLE> <A name=3DContactOfAuthor6></A> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/r027823071548868/contact.gif">= </TD> = <TD>Andreas von Deiml= ing Email:=20 <A=20 = href=3D"mailto:andreas.vondeimling@med.uni-heidelberg.de">andreas.vondeim= ling@med.uni-heidelberg.de</A></TD></TR></TBODY></TABLE> Received:=20 28 October 2008 Revised:=20 28 October 2008 Accepted:=20 28 October 2008 Published online:=20 5 November 2008 <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract A recent study = reported on=20 mutations in the active site of the isocitrate dehydrogenase = (IDH1) gene=20 in 12% of glioblastomas. All mutations detected resulted in an amino = acid=20 exchange in position 132. We analyzed the genomic region spanning wild = type R132=20 of IDH1 by direct sequencing in 685 brain tumors including 41 = pilocytic=20 astrocytomas, 12 subependymal giant cell astrocytomas, 7 pleomorphic=20 xanthoastrocytomas, 93 diffuse astrocytomas, 120 adult glioblastomas, 14 = pediatric glioblastomas, 105 oligodendrogliomas, 83 oligoastrocytomas, = 31=20 ependymomas, 58 medulloblastomas, 9 supratentorial primitive = neuroectodermal=20 tumors, 17 schwannomas, 72 meningiomas and 23 pituitary adenomas. A = total of 221=20 somatic IDH1 mutations were detected and the highest frequencies = occurred=20 in diffuse astrocytomas (68%), oligodendrogliomas (69%), = oligoastrocytomas (78%)=20 and secondary glioblastomas (88%). Primary glioblastomas and other = entities were=20 characterized by a low frequency or absence of mutations in amino acid = position=20 132 of IDH1. The very high frequency of IDH1 mutations in = WHO=20 grade II astrocytic and oligodendroglial gliomas suggests a role in = early tumor=20 development. </DIV> Keywords =20 IDH1=20 - Glioma - Progression - Astrocytoma = - Oligodendroglioma - Medulloblastoma=20 <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> Mutations in the gene encoding cytosolic NADP+ dependent isocitrate=20 dehydrogenase (IDH1) emerged as an unsuspected finding in = sequence=20 analysis of glioblastoma (GBM) [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of = isocitrate=20 to alpha-ketoglutarate thereby reducing NADP+ to NADPH. Mutations = affected the=20 amino acid arginine in position 132 of the amino acid sequence which = belongs to=20 an evolutionary conserved region locating to the binding site of = isocitrate. In=20 the vast majority of the cases wild type arginine in position 132 was = replaced=20 by histidine (R132H). The mutations reported always were heterozygous = and=20 alterations suggestive for protein inactivation such as splice site or = nonsense=20 mutations were not detected thus prompting speculations on an activating = nature=20 of the mutation [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 However, site directed mutagenesis leading to a R132E exchange in rat=20 IDP2 which is homologous to human IDH1 completely = abrogated enzyme=20 activity [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR3">3</A></CITE>].=20 Further, a mutation in porcine NADP-isocitrate dehydrogenase at position = 133,=20 R133Q, corresponding to human position 132 also resulted in = down-regulation of=20 enzyme activity [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR14">14</A></CITE>].=20 Thus the effect on enzyme activity of R132H currently is not resolved. = The subcellular localization of IDH1 encoded isocitrate = dehydrogenase=20 is the cytoplasm and the peroxisome [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR1">1</A></CITE>].=20 In the cytoplasm, the role of IDH1 protein might be to provide NADPH = under=20 conditions not favorable for generation of NADPH by the hexose = monophosphate=20 shunt. In the peroxisome IDH1 is the only known source of NADPH which is = required by several enzymes such as hydroxymethyl-CoA-, 2,4-dienoyl-CoS- = and=20 acyl-CoA-reductases. An important role of IDH1 in protection from = oxidative stress may be concluded from the demonstration of increased = resistance=20 of IDPc, the mouse homolog of IDH1, overexpressing and = sensitivity of=20 IDPc deficient NIH3T3 cells to exposure of hydrogen peroxide [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR5">5</A></CITE>].=20 Further, IDPc negative HL-60 cells exhibited augmented caspase-3 = activation upon=20 oxidative stress suggesting a role in apoptosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR4">4</A></CITE>].=20 IDH1 mutations were reported in 12% of GBM. However, the = incidence of=20 IDH1 mutations in secondary glioblastoma (secGBM) was much higher = with=20 five of six tumors carrying this alteration than that in primary = glioblastoma=20 (prGBM). By definition secGBM arise from diffuse astrocytoma WHO grade = II (A II)=20 or anaplastic astrocytoma WHO grade III (A III). This prompted us to = analyze A=20 II, A III, GBM subtypes and other brain tumors for alterations in the = mutational=20 hotspot of IDH1 with a focus on A II and A III as precursor = lesions for=20 secGBM. </DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Materials and methods</DIV> <DIV><A name=3DSec3></A> <DIV class=3DHeading3>Tumor specimens</DIV> DNA from human brain tumors diagnosed at the departments of = Neuropathology at=20 the University Bonn, the Charit=E9 Berlin, the Burdenko Neurosurgical = Institute in=20 Moscow and the University Heidelberg were analyzed. The series included = 41=20 pilocytic astrocytomas WHO grade I (PA I), 12 subependymal giant cell=20 astrocytomas WHO grade I (SEGA), 7 pleomorphic xanthoastrocytomas WHO = grade II=20 (PXA), 46 diffuse astrocytomas WHO grade II (A II), 47 anaplastic = astrocytomas=20 WHO grade III (A III), 99 primary glioblastomas WHO grade IV (prGBM), 8=20 secondary glioblastomas WHO grade IV (secGBM), 8 giant cell = glioblastomas WHO=20 grade IV (gcGBM), 14 pediatric glioblastomas (pedGBM), 5 gliosarcomas = WHO grade=20 IV (GS), 51 oligodendrogliomas WHO grade II (O II), 54 anaplastic=20 oligodendrogliomas WHO grade III (O III), 46 oligoastrocytomas WHO grade = II (OA=20 II), 37 anaplastic oligoastrocytomas WHO grade III (OA III), 6 = myxopapillary=20 ependymomas WHO grade I (E myx I), 15 ependymomas WHO grade II (E II), = 10=20 anaplastic ependymomas WHO grade III (E III), 58 medulloblastomas WHO = grade IV=20 (MB IV), 9 supratentorial primitive neuroectodermal tumors WHO grade IV=20 (PNET),17 schwannomas WHO grade I (S I), 38 meningiomas WHO grade I (M = I)=20 including the meningothelial and transitional variant, 17 atypical = meningiomas=20 WHO grade II (M II), 17 anaplastic meningiomas WHO grade III (M III) and = 23=20 pituitary adenomas WHO grade I of the null cell adenoma type (PIAD). = prGBM and=20 secGBM were defined according to Scherer [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR12">12</A></CITE>].=20 pedGBM were defined as arising in patients up to the age of 17. One = patient with=20 morphology of gcGBM was aged 10 years and therefore grouped with = pedGBM.=20 Data on TP53, combined LOH1p/19q and EGFR from tumors = included in=20 this study have been published previously [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR15">15</A></CITE>].=20 </DIV> <DIV><A name=3DSec4></A> <DIV class=3DHeading3>PCR amplification</DIV> A fragment of 129 bp length spanning the catalytic domain of = IDH1=20 including codon 132 was amplified using 60 ng each of the sense = primer=20 IDH1f CGGTCTTCAGAGAAGCCATT and the antisense primer IDH1r=20 GCAAAATCACATTATTGCCAAC. PCR using standard buffer conditions, 20 ng = of DNA=20 and GoTaq DNA Polymerase (Promega, Madison, USA) employed 35 cycles with = denaturing at 95=B0C for 30 s, annealing at 56=B0C for 40 s = and extension=20 at 72=B0C for 50 s in a total volume of 15 μl. For confirmation, the sense primer IDH1fc ACCAAATGGCACCATACGA and = antisense=20 primer IDH1rc TTCATACCTTGCTTAATGGGTGT generating a 254 bp fragment = at the=20 same PCR conditions were employed. </DIV> <DIV><A name=3DSec5></A> <DIV class=3DHeading3>Direct sequencing</DIV> A total of 2 μl of the PCR amplification product was = submitted to the=20 sequencing reaction using the BigDye Terminator v3.1 Sequencing Kit = (Applied=20 Biosystems, Foster City, USA). Twenty-five cycles were performed = employing=20 12 ng of the sense primer IDH1f CGGTCTTCAGAGAAGCCATT, with = denaturing at=20 95=B0C for 30 s, annealing at 56=B0C for 15 s and extension at = 60=B0C for=20 240 s. A second round of sequencing analysis was performed using = the=20 antisense primer IDH1rc TTCATACCTTGCTTAATGGGTGT and the sequencing = reaction=20 conditions as described above. Sequences were determined using the = semiautomated=20 sequencer (ABI 3100 Genetic Analyzer, Applied Biosystems, Foster City) = and the=20 Sequence Pilot version 3.1 (JSI-Medisys, Kippenheim, Germany) software.=20 </DIV> <DIV><A name=3DSec6></A> <DIV class=3DHeading3>Statistics</DIV> The Fisher exact test was used to examine associations between = nominal=20 variables referring to absence or presence of genetic alterations. The = t=20 test was used to examine the relation of nominal variables referring to = absence=20 or presence of genetic alterations with age within distinct tumor = groups.=20 </DIV></DIV> <DIV><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Results and discussion</DIV> <DIV><A name=3DSec8></A> <DIV class=3DHeading3>IDH1 mutations in brain tumors</DIV> <DIV class=3DPara> <DIV>Altogether, 685 tumors were analyzed and 221 mutations in = IDH1 were=20 detected. All mutations were heterozygous with one wild type allele = being=20 present. Only codon 132 of IDH1 was affected by mutations and 205 = mutations were of the R132H type, however, we also found 8 mutations = leading to=20 R132C, 4 mutations leading to R132S, 2 mutations leading to R132G, and = one=20 mutation each resulting in R132L and R132V. There was no clear = association of=20 the rare mutation types with a distinct tumor entity, although six of = the eight=20 R132C mutations were seen in astrocytomas. Type and frequency of = mutations are=20 listed in Table <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Tab1">1</A>=20 and the sequence alterations leading to the R132V are depicted in = Fig. <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Fig1">1</A>.=20 Frequent mutations of IDH1 were observed in A II (74%), A III = (62%),=20 secGBM (88%), O II (71%), O III (67%), OA II (78%) and in OA III (78%). = In order=20 to control for false positive results due to potential contamination, = all A II=20 and all O III with IDH1 mutations and all tumors with rare = IDH1=20 mutation types detected in the first round were confirmed with a second = primer=20 pair spanning a larger fragment. Because no differences between initial = and=20 confirmatory analyses were detected, the confirmatory series was not = further=20 extended.<A name=3DTab1></A> <DIV class=3DCapt>Table 1 Type of = 221=20 IDH1 mutations in brain tumors </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> Nucleotide change</TH> <TH align=3Dleft> Amino acid change</TH> <TH align=3Dleft char=3D"("> N (%) </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> G395A</TD> <TD align=3Dleft> R132H</TD> <TD align=3Dchar char=3D"("> 205 (92.7)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394T</TD> <TD align=3Dleft> R132C</TD> <TD align=3Dchar char=3D"("> 8 (3.6)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394A</TD> <TD align=3Dleft> R132S</TD> <TD align=3Dchar char=3D"("> 4 (1.8)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394G</TD> <TD align=3Dleft> R132G</TD> <TD align=3Dchar char=3D"("> 2 (0.9)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> G395T</TD> <TD align=3Dleft> R132L</TD> <TD align=3Dchar char=3D"("> 1 (0.5)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394G G395T</TD> <TD align=3Dleft> R132V</TD> <TD align=3Dchar char=3D"("> 1 (0.5)</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV>N (%) Number of tumors and percentage of mutation among all=20 mutations </DIV></DIV></DIV> <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/401_2008_455_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/r027823071548868/MediaObjects/= 401_2008_455_Fig1_HTML.gif"></DIV> <DIV class=3DCapt>Fig. 1 Example = for a=20 mutation in IDH1 in amino acid position 132. wt Wild type = sequence=20 (green background, mut mutated sequence (shaded in = red)=20 </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>The frequency of mutations in PNET (33%) and gcGBM (25%) is = noteworthy,=20 although, the number of tumors included in the study is too low for a = clear=20 statement. No IDH1 mutations were detected in SEGA, PXA, GS, E = myx I, E=20 II, E III, MB IV S I, M I, M II, M III and PIAD. Only single or few = mutations=20 occurred in PA I (3%), prGBM (7%) and pedGBM (7%). Constitutional DNA = from=20 peripheral leukocytes was examined from all patients with a tumor = carrying an=20 IDH1 mutation. In all patients with alterations in IDH1 = the=20 mutation was confirmed to be of somatic origin. A compilation of = IDH1=20 mutations in our series of human brain tumors is given in Table <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Tab2">2</A>.<A=20 name=3DTab2></A> <DIV class=3DCapt>Table 2 = IDH1=20 mutations in 685 brain tumors </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH rowSpan=3D2 align=3Dleft> Diagnosis</TH> <TH rowSpan=3D2 align=3Dleft char=3D"."> N </TH> <TH colSpan=3D3 align=3Dleft char=3D"."> IDH1 </TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"."> Wt</TH> <TH align=3Dleft char=3D"."> Mut</TH> <TH align=3Dleft char=3D"."> Mut (%)</TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> Pilocytic astrocytoma WHO grade I (PA I)</TD> <TD align=3Dchar char=3D"."> 41</TD> <TD align=3Dchar char=3D"."> 40</TD> <TD align=3Dchar char=3D"."> 1</TD> <TD align=3Dchar char=3D"."> 2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Subependymal giant cell astrocytoma WHO grade I (SEGA = I)</TD> <TD align=3Dchar char=3D"."> 12</TD> <TD align=3Dchar char=3D"."> 12</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Pleomorphic xanthoastrocytoma WHO grade II (PXA II)</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Astrocytoma WHO grade II (A II)</TD> <TD align=3Dchar char=3D"."> 46</TD> <TD align=3Dchar char=3D"."> 13</TD> <TD align=3Dchar char=3D"."> 34</TD> <TD align=3Dchar char=3D"."> 74</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic astrocytoma WHO grade III (A III)</TD> <TD align=3Dchar char=3D"."> 47</TD> <TD align=3Dchar char=3D"."> 18</TD> <TD align=3Dchar char=3D"."> 29</TD> <TD align=3Dchar char=3D"."> 62</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Primary Glioblastoma WHO grade IV (prGBM)</TD> <TD align=3Dchar char=3D"."> 99</TD> <TD align=3Dchar char=3D"."> 92</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 7</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Secondary glioblastoma WHO grade IV (secGBM)</TD> <TD align=3Dchar char=3D"."> 8</TD> <TD align=3Dchar char=3D"."> 1</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 88</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Giant cell glioblastoma WHO grade IV (gcGBM)</TD> <TD align=3Dchar char=3D"."> 8</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 2</TD> <TD align=3Dchar char=3D"."> 25</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Pediatric Glioblastoma WHO grade IV (pedGBM)</TD> <TD align=3Dchar char=3D"."> 14</TD> <TD align=3Dchar char=3D"."> 13</TD> <TD align=3Dchar char=3D"."> 1</TD> <TD align=3Dchar char=3D"."> 7</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Gliosarcoma WHO grade IV (GS)</TD> <TD align=3Dchar char=3D"."> 5</TD> <TD align=3Dchar char=3D"."> 5</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> =96</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Oligodendroglioma WHO grade II (O II)</TD> <TD align=3Dchar char=3D"."> 51</TD> <TD align=3Dchar char=3D"."> 15</TD> <TD align=3Dchar char=3D"."> 36</TD> <TD align=3Dchar char=3D"."> 71</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic oligodendroglioma WHO grade III (O III)</TD> <TD align=3Dchar char=3D"."> 54</TD> <TD align=3Dchar char=3D"."> 18</TD> <TD align=3Dchar char=3D"."> 36</TD> <TD align=3Dchar char=3D"."> 67</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Oligoastrocytoma WHO grade II (OA II)</TD> <TD align=3Dchar char=3D"."> 46</TD> <TD align=3Dchar char=3D"."> 10</TD> <TD align=3Dchar char=3D"."> 36</TD> <TD align=3Dchar char=3D"."> 78</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic oligoastrocytoma WHO grade III (OA III)</TD> <TD align=3Dchar char=3D"."> 37</TD> <TD align=3Dchar char=3D"."> 8</TD> <TD align=3Dchar char=3D"."> 29</TD> <TD align=3Dchar char=3D"."> 78</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Myxopapillary ependymoma WHO grade I (E myx I)</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> =96</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Ependymoma WHO grade II (E II)</TD> <TD align=3Dchar char=3D"."> 15</TD> <TD align=3Dchar char=3D"."> 15</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic ependymoma WHO grade III (E III)</TD> <TD align=3Dchar char=3D"."> 10</TD> <TD align=3Dchar char=3D"."> 10</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Medulloblastoma WHO grade IV (MB IV)</TD> <TD align=3Dchar char=3D"."> 58</TD> <TD align=3Dchar char=3D"."> 58</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Primitive neuroectodermal tumor WHO grade IV (PNET)</TD> <TD align=3Dchar char=3D"."> 9</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 3</TD> <TD align=3Dchar char=3D"."> 33</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Schwannoma WHO grade I (S I)</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Meningioma WHO grade I (M I)</TD> <TD align=3Dchar char=3D"."> 38</TD> <TD align=3Dchar char=3D"."> 38</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Atypical meningioma WHO grade II (M II)</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic meningioma WHO grade III (M III)</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Pituitary adenoma WHO grade I (PIAD)</TD> <TD align=3Dchar char=3D"."> 23</TD> <TD align=3Dchar char=3D"."> 23</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV>N Number of tumors, IDH1 isocitrate dehydrogenase 1,=20 Wt wild type, Mut mutated, Mut (%) percentage of = tumors=20 with mutation. Percentages are given for entities with seven or more = tumors=20 included </DIV></DIV></DIV></DIV></DIV> Unexpected findings were the high frequency of IDH1 mutations = in=20 diffuse astrocytic, oligodendroglial and mixed gliomas of the WHO grades = II and=20 III. The WHO grade II tumors already carry IDH1 mutations thereby = demonstrating that this alteration does not occur during tumor = progression. In=20 contrast, the high incidence of IDH1 mutations in A II, O II and = OA II=20 may allow the speculation, that this mutation is involved in early steps = of=20 tumorigenesis. The frequency of mutations in these tumors exceeded the = one=20 observed in GBM. However, IDH1 mutations showed an unbalanced=20 distribution among the different subtypes of GBM. A very high frequency = was=20 observed in secGBM confirming the previous report [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 In contrast, only few prGBM carried IDH1 mutations. This = distribution may=20 even suggest that in those prGBM with IDH1 mutation, the = diagnosis of a=20 previous lower grade astrocytoma has been missed. No mutations were = detected in=20 GS. The analysis of PIAD was of interest because of the observation, that = IDH1 expression was strongly up-regulated in non-functional PIAD=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR7">7</A></CITE>].=20 While IDH1 mutations have been discussed to be of activating = nature=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>],=20 they might also have an effect on transcription or stability of mRNA. = However,=20 analysis of 23 PIAD lacking expression of pituitary hormones revealed no = mutation, suggesting that up-regulated IDH1 expression in these = tumors is=20 independent to the status in the mutational hotspot coding for amino = acid=20 position 132. </DIV> <DIV><A name=3DSec9></A> <DIV class=3DHeading3>Distribution of IDH1, TP53 and EGFR mutations and = of=20 LOH1p/19q in gliomas</DIV> IDH1 mutations did not show any association with TP53 = mutations=20 or LOH1p/19q in A II, A III, O II, O III and mixed OA II and OA III. On = the=20 other hand LOH1p/19q typically is detected in oligodendrogliomas but = rare in=20 astrocytomas and, vice versa, TP53 mutations are frequent in = astrocytomas=20 but rare in oligodendrogliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>].=20 Both alterations are quite frequent in oligoastrocytomas but usually do = not=20 co-occur. Thus, the hallmark molecular findings in these tumors so far=20 segregated between oligodendroglial and astrocytic tumors and this = distribution=20 suggested that these tumors originated from different precursor = populations. In=20 contrast, IDH1 mutations seem to group together A II, A III, O = II, O III,=20 OA II and OA III and suggest a common pathway in their genesis. It might = be that=20 IDH1 mutations occur in the O2A precursor cell giving rise to = astrocytic=20 and oligodendroglial lineage [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR11">11</A></CITE>]=20 and that TP53 mutations and LOH1p/19q arise at a later point in = cells=20 already committed to either lineage. However, such speculation implies = that=20 oligodendroglial tumors arise from precursor cells of oligodendroglia = and this=20 has not yet been demonstrated. With regard to GBM it is of interest that IDH1 mutations are = much more=20 frequent in A II and A III than in prGBM which parallels the = distribution of=20 TP53 mutations in these entities. In contrast, the frequency of = mutations=20 in both, IDH1 and TP53 are high in secGBM as can be = expected from=20 tumors which by definition progress from A II or A III. IDH1 mutations and EGFR amplification were inversely = associated=20 upon pooling all GBM. However, this is to be expected given the high = frequency=20 of IDH1 in secGBM and the well established absence of EGFR = amplification=20 in this subgroup [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR17">17</A></CITE>].=20 Within the prGBM, there was no association between IDH1 and EGFR=20 mutational status. <DIV class=3DPara> <DIV>Mutations of single genes or disruption of signal transduction = pathways=20 have been used to establish models for the molecular subclassification = of=20 gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR17">17</A></CITE>].=20 The addition of the mutational status of IDH1 adds to these = models. For=20 example, the frequency of IDH1 mutations clearly differs between = secGBM=20 and pedGBM both of which are characterized by frequent TP53 = mutations and=20 rare or absent EGFR amplifications. In contrast, = oligodendroglioma,=20 oligoastrocytoma and astrocytoma which so far were on a molecular basis=20 distinguished on their frequency of TP53 mutations and LOH1p/19q = are=20 unified by a high frequency of IDH1 mutations in all three = entities. Data=20 on TP53, combined LOH1p/19q and EGFR from tumors included = in this=20 study have been published previously [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR15">15</A></CITE>]=20 and are compiled in Table <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Tab3">3</A>.<A=20 name=3DTab3></A> <DIV class=3DCapt>Table 3 Incidence of=20 mutations in IDH1, TP53 and EGFR and occurrence of = LOH=20 1p/19q in gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR15">15</A></CITE>]=20 </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> </TH> <TH align=3Dleft char=3D"("> IDH1 </TH> <TH align=3Dleft char=3D"("> TP53 </TH> <TH align=3Dleft char=3D"("> LOH 1p/19q</TH> <TH align=3Dleft char=3D"("> EGFRamp </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Glioblastoma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> pedGBM</TD> <TD align=3Dchar char=3D"("> 1/14 (7%)</TD> <TD align=3Dchar char=3D"("> 2/3</TD> <TD align=3Dchar char=3D"("> 0/3</TD> <TD align=3Dchar char=3D"("> 0/2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> prGBM</TD> <TD align=3Dchar char=3D"("> 7/99 (7%)</TD> <TD align=3Dchar char=3D"("> 15/88 (17%)</TD> <TD align=3Dchar char=3D"("> 6/73 (8%)</TD> <TD align=3Dchar char=3D"("> 26/71 (37%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> secGBM</TD> <TD align=3Dchar char=3D"("> 8/8 (88%)</TD> <TD align=3Dchar char=3D"("> 7/8 (88%)</TD> <TD align=3Dchar char=3D"("> 1/8 (13%)</TD> <TD align=3Dchar char=3D"("> 0/8 0(%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> gcGBM</TD> <TD align=3Dchar char=3D"("> 2/8 (25%)</TD> <TD align=3Dchar char=3D"("> 6/7 (86%)</TD> <TD align=3Dchar char=3D"("> 0/6</TD> <TD align=3Dchar char=3D"("> 0/7 (0%)</TD></TR> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Astrocytoma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> A II</TD> <TD align=3Dchar char=3D"("> 33/46 (79%)</TD> <TD align=3Dchar char=3D"("> 13/25 (52%)</TD> <TD align=3Dchar char=3D"("> 6/34 (18%)</TD> <TD align=3Dchar char=3D"("> 0/17 (0%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> A III</TD> <TD align=3Dchar char=3D"("> 29/47 (62%)</TD> <TD align=3Dchar char=3D"("> 13/30 (43%)</TD> <TD align=3Dchar char=3D"("> 5/43 (12%)</TD> <TD align=3Dchar char=3D"("> 1/22 (5%)</TD></TR> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Oligodendroglioma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> O II</TD> <TD align=3Dchar char=3D"("> 36/51 (71%)</TD> <TD align=3Dchar char=3D"("> 3/31 (10%)</TD> <TD align=3Dchar char=3D"("> 30/50 (60%)</TD> <TD align=3Dchar char=3D"("> 0/11 (0%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> O III</TD> <TD align=3Dchar char=3D"("> 36/54 (67%)</TD> <TD align=3Dchar char=3D"("> 4/31 (13%)</TD> <TD align=3Dchar char=3D"("> 35/53 (66%)</TD> <TD align=3Dchar char=3D"("> 0/4</TD></TR> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Oligoastrocytoma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> OA II</TD> <TD align=3Dchar char=3D"("> 36/46 (78%)</TD> <TD align=3Dchar char=3D"("> 6/26 (23%)</TD> <TD align=3Dchar char=3D"("> 24/45 (53%)</TD> <TD align=3Dchar char=3D"("> 0/10 (0%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> OA III</TD> <TD align=3Dchar char=3D"("> 29/37 (78%)</TD> <TD align=3Dchar char=3D"("> 6/22 (27%)</TD> <TD align=3Dchar char=3D"("> 26/36 (72%)</TD> <TD align=3Dchar char=3D"("> 0/8 (0%)</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV>Given are the numbers of tumors with mutations among the tumors = examined=20 for this parameter, and in brackets percentages of mutations in this = series=20 </DIV></DIV> <DIV class=3DCaptCont> <DIV>IDH1 Isocitrate dehydrogenase 1, TP53 tumor protein = 53,=20 LOH 1p/19q combined loss of heterozygosity on chromosomal arms 1p = and=20 19q, EGFRamp amplification of the EGFR gene, pedGBM = pediatric glioblastoma WHO grade IV, prGBM primary glioblastoma = WHO grade=20 IV, secGBM secondary glioblastoma WHO grade IV, gcGBM = giant cell=20 glioblastoma WHO grade IV, A II astrocytoma WHO grade II, A = III=20 anaplastic astrocytoma WHO grade III, O II oligodendroglioma WHO = grade=20 II, O III anaplastic oligodendroglioma WHO grade III, OA = II=20 oligoastrocytoma WHO grade II, OA III anaplastic oligoastrocytoma = WHO=20 grade III </DIV></DIV></DIV></DIV></DIV></DIV> <DIV><A name=3DSec10></A> <DIV class=3DHeading3>Association of IDH1 mutations with age</DIV> There was a strong association of age and presence or absence of = IDH1=20 mutations in patients with prGBM. Patients with prGBM and IDH1mut = averaged 40.3 years and those with IDH1wt averaged = 52.6 years=20 (P < 0.005). This confirms previous observations = [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 Patients with A III and IDH1mut averaged 35.0 years and = those with=20 IDH1wt averaged 44.4 years (P < 0.05). = Patients=20 with O III and IDH1mut averaged 47.7 years and those with=20 IDH1wt averaged 54.8 years (not significant). Patients with = OA III=20 and IDH1mut averaged 44.3 years and those with IDH1wt = averaged 63.5 years (P < 0.0005). The average = ages in=20 patients with A II, O II and OA II did not differ significantly in the = groups=20 with and without IDH1 mutations. An explanation for the association of=20 IDH1 mutations with age only in the highly malignant entities may = be that=20 these tumors sometimes are under-diagnosed due to lack of presence of = necrosis=20 resulting from tumor sampling. Therefore, these entities might contain = some=20 prGBM which do have a low frequency of IDH1 mutations but = predominantly=20 occur in patients of advanced age. Interestingly, no significant = difference is=20 observed in O III which among anaplastic astrocytic and oligodendroglial = tumors=20 poses least problems in differentiating from prGBM. </DIV> <DIV><A name=3DSec11></A> <DIV class=3DHeading3>IDH1 and tumor progression</DIV> IDH1 mutations were frequent in A II (74%) suggesting that = this=20 alteration already is of importance for earlier steps in tumor = formation.=20 Mutations in A III (62%) were somewhat less frequent than in A II, = however, this=20 difference was not significant. IDH1 mutations in secGBM (88%) = were very=20 frequent. In contrast, only few IDH1 mutations were detected in = prGBM=20 (7%). Thus, all tumors belonging to the progression series from A II and = A III=20 to secGBM exhibited IDH1 mutations in a high and comparable = frequency.=20 Similar to A II, O II (71%) and OA II (78%) exhibit a high frequency of=20 IDH1 mutations. Comparable frequencies are observed in O III = (67%) and OA=20 III (78%). These findings suggest that IDH1 mutations are more = likely to=20 be important for tumor formation in diffuse astrocytomas and = oligodendroglial=20 tumors than for progression towards malignancy. The evaluation of a = prognostic=20 and predictive value of IDH1 mutations will require analyses of = large and=20 well-documented trial studies with focus on diffuse gliomas including A = II, A=20 III, O II, O III, OA II and OA III. </DIV> <DIV><A name=3DSec12></A> <DIV class=3DHeading3>Conclusions</DIV> IDH1 mutations typically occur in diffuse gliomas of = astrocytic,=20 oligodendroglial and mixed oligoastroglial differentiation and in = glioblastomas=20 having progressed from these tumors. This is contrasted by the low = frequency of=20 IDH1 mutations in primary glioblastoma. The very high frequency = of=20 IDH1 mutations in WHO grade II astrocytic and oligodendroglial = gliomas=20 suggests a role in early tumor development. </DIV></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments Th= is work=20 was supported by the Bundesministerium f=FCr Bildung und Forschung = (BMBF). We wish=20 to thank K. Lindenberg, U. Ernst and F. 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From: Subject: 10.1007/s00401-008-0455-2 Date: Wed, 4 Mar 2009 16:37:16 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C99CE7.7A6BBFB0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C99CE7.7A6BBFB0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/r027823071548868/fulltext.html 10.1007/s00401-008-0455-2</TITLE= > <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18372"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Acta Neuropathologica</TD></TR> <TR> <TD>=A9 Springer-Verlag 2008</TD></TR> <TR> <TD>10.1007/s00401-008-0455-2</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Original Paper</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Analysis of the IDH1 = codon 132=20 mutation in brain tumors </DIV> J=F6rg Balss1, = Jochen Meyer1,=20 Wolf Mueller2, Andrey Korshunov2, 1,=20 Christian Hartmann2, 1 and = Andreas von Deimling2,=20 1 <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#ContactOfAuthor6"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/r027823071548868/contact.gif">= </A> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff2></A>(1) </TD> <TD>Clinical Cooperation Unit = Neuropathology G380,=20 German Cancer Research Center, 69120 Heidelberg,=20 Germany</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff1></A>(2) </TD> <TD>Department of Neuropathology, = Institute of=20 Pathology, Ruprecht-Karls-Universit=E4t Heidelberg, Im Neuenheimer = Feld=20 220/221, 69120 Heidelberg, = Germany</TD></TR></TBODY></TABLE> <A name=3DContactOfAuthor6></A> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/r027823071548868/contact.gif">= </TD> = <TD>Andreas von Deiml= ing Email:=20 <A=20 = href=3D"mailto:andreas.vondeimling@med.uni-heidelberg.de">andreas.vondeim= ling@med.uni-heidelberg.de</A></TD></TR></TBODY></TABLE> Received:=20 28 October 2008 Revised:=20 28 October 2008 Accepted:=20 28 October 2008 Published online:=20 5 November 2008 <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract A recent study = reported on=20 mutations in the active site of the isocitrate dehydrogenase = (IDH1) gene=20 in 12% of glioblastomas. All mutations detected resulted in an amino = acid=20 exchange in position 132. We analyzed the genomic region spanning wild = type R132=20 of IDH1 by direct sequencing in 685 brain tumors including 41 = pilocytic=20 astrocytomas, 12 subependymal giant cell astrocytomas, 7 pleomorphic=20 xanthoastrocytomas, 93 diffuse astrocytomas, 120 adult glioblastomas, 14 = pediatric glioblastomas, 105 oligodendrogliomas, 83 oligoastrocytomas, = 31=20 ependymomas, 58 medulloblastomas, 9 supratentorial primitive = neuroectodermal=20 tumors, 17 schwannomas, 72 meningiomas and 23 pituitary adenomas. A = total of 221=20 somatic IDH1 mutations were detected and the highest frequencies = occurred=20 in diffuse astrocytomas (68%), oligodendrogliomas (69%), = oligoastrocytomas (78%)=20 and secondary glioblastomas (88%). Primary glioblastomas and other = entities were=20 characterized by a low frequency or absence of mutations in amino acid = position=20 132 of IDH1. The very high frequency of IDH1 mutations in = WHO=20 grade II astrocytic and oligodendroglial gliomas suggests a role in = early tumor=20 development. </DIV> Keywords =20 IDH1=20 - Glioma - Progression - Astrocytoma = - Oligodendroglioma - Medulloblastoma=20 <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> Mutations in the gene encoding cytosolic NADP+ dependent isocitrate=20 dehydrogenase (IDH1) emerged as an unsuspected finding in = sequence=20 analysis of glioblastoma (GBM) [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of = isocitrate=20 to alpha-ketoglutarate thereby reducing NADP+ to NADPH. Mutations = affected the=20 amino acid arginine in position 132 of the amino acid sequence which = belongs to=20 an evolutionary conserved region locating to the binding site of = isocitrate. In=20 the vast majority of the cases wild type arginine in position 132 was = replaced=20 by histidine (R132H). The mutations reported always were heterozygous = and=20 alterations suggestive for protein inactivation such as splice site or = nonsense=20 mutations were not detected thus prompting speculations on an activating = nature=20 of the mutation [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 However, site directed mutagenesis leading to a R132E exchange in rat=20 IDP2 which is homologous to human IDH1 completely = abrogated enzyme=20 activity [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR3">3</A></CITE>].=20 Further, a mutation in porcine NADP-isocitrate dehydrogenase at position = 133,=20 R133Q, corresponding to human position 132 also resulted in = down-regulation of=20 enzyme activity [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR14">14</A></CITE>].=20 Thus the effect on enzyme activity of R132H currently is not resolved. = The subcellular localization of IDH1 encoded isocitrate = dehydrogenase=20 is the cytoplasm and the peroxisome [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR1">1</A></CITE>].=20 In the cytoplasm, the role of IDH1 protein might be to provide NADPH = under=20 conditions not favorable for generation of NADPH by the hexose = monophosphate=20 shunt. In the peroxisome IDH1 is the only known source of NADPH which is = required by several enzymes such as hydroxymethyl-CoA-, 2,4-dienoyl-CoS- = and=20 acyl-CoA-reductases. An important role of IDH1 in protection from = oxidative stress may be concluded from the demonstration of increased = resistance=20 of IDPc, the mouse homolog of IDH1, overexpressing and = sensitivity of=20 IDPc deficient NIH3T3 cells to exposure of hydrogen peroxide [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR5">5</A></CITE>].=20 Further, IDPc negative HL-60 cells exhibited augmented caspase-3 = activation upon=20 oxidative stress suggesting a role in apoptosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR4">4</A></CITE>].=20 IDH1 mutations were reported in 12% of GBM. However, the = incidence of=20 IDH1 mutations in secondary glioblastoma (secGBM) was much higher = with=20 five of six tumors carrying this alteration than that in primary = glioblastoma=20 (prGBM). By definition secGBM arise from diffuse astrocytoma WHO grade = II (A II)=20 or anaplastic astrocytoma WHO grade III (A III). This prompted us to = analyze A=20 II, A III, GBM subtypes and other brain tumors for alterations in the = mutational=20 hotspot of IDH1 with a focus on A II and A III as precursor = lesions for=20 secGBM. </DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Materials and methods</DIV> <DIV><A name=3DSec3></A> <DIV class=3DHeading3>Tumor specimens</DIV> DNA from human brain tumors diagnosed at the departments of = Neuropathology at=20 the University Bonn, the Charit=E9 Berlin, the Burdenko Neurosurgical = Institute in=20 Moscow and the University Heidelberg were analyzed. The series included = 41=20 pilocytic astrocytomas WHO grade I (PA I), 12 subependymal giant cell=20 astrocytomas WHO grade I (SEGA), 7 pleomorphic xanthoastrocytomas WHO = grade II=20 (PXA), 46 diffuse astrocytomas WHO grade II (A II), 47 anaplastic = astrocytomas=20 WHO grade III (A III), 99 primary glioblastomas WHO grade IV (prGBM), 8=20 secondary glioblastomas WHO grade IV (secGBM), 8 giant cell = glioblastomas WHO=20 grade IV (gcGBM), 14 pediatric glioblastomas (pedGBM), 5 gliosarcomas = WHO grade=20 IV (GS), 51 oligodendrogliomas WHO grade II (O II), 54 anaplastic=20 oligodendrogliomas WHO grade III (O III), 46 oligoastrocytomas WHO grade = II (OA=20 II), 37 anaplastic oligoastrocytomas WHO grade III (OA III), 6 = myxopapillary=20 ependymomas WHO grade I (E myx I), 15 ependymomas WHO grade II (E II), = 10=20 anaplastic ependymomas WHO grade III (E III), 58 medulloblastomas WHO = grade IV=20 (MB IV), 9 supratentorial primitive neuroectodermal tumors WHO grade IV=20 (PNET),17 schwannomas WHO grade I (S I), 38 meningiomas WHO grade I (M = I)=20 including the meningothelial and transitional variant, 17 atypical = meningiomas=20 WHO grade II (M II), 17 anaplastic meningiomas WHO grade III (M III) and = 23=20 pituitary adenomas WHO grade I of the null cell adenoma type (PIAD). = prGBM and=20 secGBM were defined according to Scherer [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR12">12</A></CITE>].=20 pedGBM were defined as arising in patients up to the age of 17. One = patient with=20 morphology of gcGBM was aged 10 years and therefore grouped with = pedGBM.=20 Data on TP53, combined LOH1p/19q and EGFR from tumors = included in=20 this study have been published previously [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR15">15</A></CITE>].=20 </DIV> <DIV><A name=3DSec4></A> <DIV class=3DHeading3>PCR amplification</DIV> A fragment of 129 bp length spanning the catalytic domain of = IDH1=20 including codon 132 was amplified using 60 ng each of the sense = primer=20 IDH1f CGGTCTTCAGAGAAGCCATT and the antisense primer IDH1r=20 GCAAAATCACATTATTGCCAAC. PCR using standard buffer conditions, 20 ng = of DNA=20 and GoTaq DNA Polymerase (Promega, Madison, USA) employed 35 cycles with = denaturing at 95=B0C for 30 s, annealing at 56=B0C for 40 s = and extension=20 at 72=B0C for 50 s in a total volume of 15 μl. For confirmation, the sense primer IDH1fc ACCAAATGGCACCATACGA and = antisense=20 primer IDH1rc TTCATACCTTGCTTAATGGGTGT generating a 254 bp fragment = at the=20 same PCR conditions were employed. </DIV> <DIV><A name=3DSec5></A> <DIV class=3DHeading3>Direct sequencing</DIV> A total of 2 μl of the PCR amplification product was = submitted to the=20 sequencing reaction using the BigDye Terminator v3.1 Sequencing Kit = (Applied=20 Biosystems, Foster City, USA). Twenty-five cycles were performed = employing=20 12 ng of the sense primer IDH1f CGGTCTTCAGAGAAGCCATT, with = denaturing at=20 95=B0C for 30 s, annealing at 56=B0C for 15 s and extension at = 60=B0C for=20 240 s. A second round of sequencing analysis was performed using = the=20 antisense primer IDH1rc TTCATACCTTGCTTAATGGGTGT and the sequencing = reaction=20 conditions as described above. Sequences were determined using the = semiautomated=20 sequencer (ABI 3100 Genetic Analyzer, Applied Biosystems, Foster City) = and the=20 Sequence Pilot version 3.1 (JSI-Medisys, Kippenheim, Germany) software.=20 </DIV> <DIV><A name=3DSec6></A> <DIV class=3DHeading3>Statistics</DIV> The Fisher exact test was used to examine associations between = nominal=20 variables referring to absence or presence of genetic alterations. The = t=20 test was used to examine the relation of nominal variables referring to = absence=20 or presence of genetic alterations with age within distinct tumor = groups.=20 </DIV></DIV> <DIV><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Results and discussion</DIV> <DIV><A name=3DSec8></A> <DIV class=3DHeading3>IDH1 mutations in brain tumors</DIV> <DIV class=3DPara> <DIV>Altogether, 685 tumors were analyzed and 221 mutations in = IDH1 were=20 detected. All mutations were heterozygous with one wild type allele = being=20 present. Only codon 132 of IDH1 was affected by mutations and 205 = mutations were of the R132H type, however, we also found 8 mutations = leading to=20 R132C, 4 mutations leading to R132S, 2 mutations leading to R132G, and = one=20 mutation each resulting in R132L and R132V. There was no clear = association of=20 the rare mutation types with a distinct tumor entity, although six of = the eight=20 R132C mutations were seen in astrocytomas. Type and frequency of = mutations are=20 listed in Table <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Tab1">1</A>=20 and the sequence alterations leading to the R132V are depicted in = Fig. <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Fig1">1</A>.=20 Frequent mutations of IDH1 were observed in A II (74%), A III = (62%),=20 secGBM (88%), O II (71%), O III (67%), OA II (78%) and in OA III (78%). = In order=20 to control for false positive results due to potential contamination, = all A II=20 and all O III with IDH1 mutations and all tumors with rare = IDH1=20 mutation types detected in the first round were confirmed with a second = primer=20 pair spanning a larger fragment. Because no differences between initial = and=20 confirmatory analyses were detected, the confirmatory series was not = further=20 extended.<A name=3DTab1></A> <DIV class=3DCapt>Table 1 Type of = 221=20 IDH1 mutations in brain tumors </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> Nucleotide change</TH> <TH align=3Dleft> Amino acid change</TH> <TH align=3Dleft char=3D"("> N (%) </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> G395A</TD> <TD align=3Dleft> R132H</TD> <TD align=3Dchar char=3D"("> 205 (92.7)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394T</TD> <TD align=3Dleft> R132C</TD> <TD align=3Dchar char=3D"("> 8 (3.6)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394A</TD> <TD align=3Dleft> R132S</TD> <TD align=3Dchar char=3D"("> 4 (1.8)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394G</TD> <TD align=3Dleft> R132G</TD> <TD align=3Dchar char=3D"("> 2 (0.9)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> G395T</TD> <TD align=3Dleft> R132L</TD> <TD align=3Dchar char=3D"("> 1 (0.5)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> C394G G395T</TD> <TD align=3Dleft> R132V</TD> <TD align=3Dchar char=3D"("> 1 (0.5)</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV>N (%) Number of tumors and percentage of mutation among all=20 mutations </DIV></DIV></DIV> <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/401_2008_455_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/r027823071548868/MediaObjects/= 401_2008_455_Fig1_HTML.gif"></DIV> <DIV class=3DCapt>Fig. 1 Example = for a=20 mutation in IDH1 in amino acid position 132. wt Wild type = sequence=20 (green background, mut mutated sequence (shaded in = red)=20 </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>The frequency of mutations in PNET (33%) and gcGBM (25%) is = noteworthy,=20 although, the number of tumors included in the study is too low for a = clear=20 statement. No IDH1 mutations were detected in SEGA, PXA, GS, E = myx I, E=20 II, E III, MB IV S I, M I, M II, M III and PIAD. Only single or few = mutations=20 occurred in PA I (3%), prGBM (7%) and pedGBM (7%). Constitutional DNA = from=20 peripheral leukocytes was examined from all patients with a tumor = carrying an=20 IDH1 mutation. In all patients with alterations in IDH1 = the=20 mutation was confirmed to be of somatic origin. A compilation of = IDH1=20 mutations in our series of human brain tumors is given in Table <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Tab2">2</A>.<A=20 name=3DTab2></A> <DIV class=3DCapt>Table 2 = IDH1=20 mutations in 685 brain tumors </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."> <COL align=3Dchar char=3D"."></COLGROUP> <THEAD> <TR class=3Dheader> <TH rowSpan=3D2 align=3Dleft> Diagnosis</TH> <TH rowSpan=3D2 align=3Dleft char=3D"."> N </TH> <TH colSpan=3D3 align=3Dleft char=3D"."> IDH1 </TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"."> Wt</TH> <TH align=3Dleft char=3D"."> Mut</TH> <TH align=3Dleft char=3D"."> Mut (%)</TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> Pilocytic astrocytoma WHO grade I (PA I)</TD> <TD align=3Dchar char=3D"."> 41</TD> <TD align=3Dchar char=3D"."> 40</TD> <TD align=3Dchar char=3D"."> 1</TD> <TD align=3Dchar char=3D"."> 2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Subependymal giant cell astrocytoma WHO grade I (SEGA = I)</TD> <TD align=3Dchar char=3D"."> 12</TD> <TD align=3Dchar char=3D"."> 12</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Pleomorphic xanthoastrocytoma WHO grade II (PXA II)</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Astrocytoma WHO grade II (A II)</TD> <TD align=3Dchar char=3D"."> 46</TD> <TD align=3Dchar char=3D"."> 13</TD> <TD align=3Dchar char=3D"."> 34</TD> <TD align=3Dchar char=3D"."> 74</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic astrocytoma WHO grade III (A III)</TD> <TD align=3Dchar char=3D"."> 47</TD> <TD align=3Dchar char=3D"."> 18</TD> <TD align=3Dchar char=3D"."> 29</TD> <TD align=3Dchar char=3D"."> 62</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Primary Glioblastoma WHO grade IV (prGBM)</TD> <TD align=3Dchar char=3D"."> 99</TD> <TD align=3Dchar char=3D"."> 92</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 7</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Secondary glioblastoma WHO grade IV (secGBM)</TD> <TD align=3Dchar char=3D"."> 8</TD> <TD align=3Dchar char=3D"."> 1</TD> <TD align=3Dchar char=3D"."> 7</TD> <TD align=3Dchar char=3D"."> 88</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Giant cell glioblastoma WHO grade IV (gcGBM)</TD> <TD align=3Dchar char=3D"."> 8</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 2</TD> <TD align=3Dchar char=3D"."> 25</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Pediatric Glioblastoma WHO grade IV (pedGBM)</TD> <TD align=3Dchar char=3D"."> 14</TD> <TD align=3Dchar char=3D"."> 13</TD> <TD align=3Dchar char=3D"."> 1</TD> <TD align=3Dchar char=3D"."> 7</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Gliosarcoma WHO grade IV (GS)</TD> <TD align=3Dchar char=3D"."> 5</TD> <TD align=3Dchar char=3D"."> 5</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> =96</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Oligodendroglioma WHO grade II (O II)</TD> <TD align=3Dchar char=3D"."> 51</TD> <TD align=3Dchar char=3D"."> 15</TD> <TD align=3Dchar char=3D"."> 36</TD> <TD align=3Dchar char=3D"."> 71</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic oligodendroglioma WHO grade III (O III)</TD> <TD align=3Dchar char=3D"."> 54</TD> <TD align=3Dchar char=3D"."> 18</TD> <TD align=3Dchar char=3D"."> 36</TD> <TD align=3Dchar char=3D"."> 67</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Oligoastrocytoma WHO grade II (OA II)</TD> <TD align=3Dchar char=3D"."> 46</TD> <TD align=3Dchar char=3D"."> 10</TD> <TD align=3Dchar char=3D"."> 36</TD> <TD align=3Dchar char=3D"."> 78</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic oligoastrocytoma WHO grade III (OA III)</TD> <TD align=3Dchar char=3D"."> 37</TD> <TD align=3Dchar char=3D"."> 8</TD> <TD align=3Dchar char=3D"."> 29</TD> <TD align=3Dchar char=3D"."> 78</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Myxopapillary ependymoma WHO grade I (E myx I)</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> =96</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Ependymoma WHO grade II (E II)</TD> <TD align=3Dchar char=3D"."> 15</TD> <TD align=3Dchar char=3D"."> 15</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic ependymoma WHO grade III (E III)</TD> <TD align=3Dchar char=3D"."> 10</TD> <TD align=3Dchar char=3D"."> 10</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Medulloblastoma WHO grade IV (MB IV)</TD> <TD align=3Dchar char=3D"."> 58</TD> <TD align=3Dchar char=3D"."> 58</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Primitive neuroectodermal tumor WHO grade IV (PNET)</TD> <TD align=3Dchar char=3D"."> 9</TD> <TD align=3Dchar char=3D"."> 6</TD> <TD align=3Dchar char=3D"."> 3</TD> <TD align=3Dchar char=3D"."> 33</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Schwannoma WHO grade I (S I)</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Meningioma WHO grade I (M I)</TD> <TD align=3Dchar char=3D"."> 38</TD> <TD align=3Dchar char=3D"."> 38</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Atypical meningioma WHO grade II (M II)</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Anaplastic meningioma WHO grade III (M III)</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 17</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> Pituitary adenoma WHO grade I (PIAD)</TD> <TD align=3Dchar char=3D"."> 23</TD> <TD align=3Dchar char=3D"."> 23</TD> <TD align=3Dchar char=3D"."> 0</TD> <TD align=3Dchar char=3D"."> 0</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV>N Number of tumors, IDH1 isocitrate dehydrogenase 1,=20 Wt wild type, Mut mutated, Mut (%) percentage of = tumors=20 with mutation. Percentages are given for entities with seven or more = tumors=20 included </DIV></DIV></DIV></DIV></DIV> Unexpected findings were the high frequency of IDH1 mutations = in=20 diffuse astrocytic, oligodendroglial and mixed gliomas of the WHO grades = II and=20 III. The WHO grade II tumors already carry IDH1 mutations thereby = demonstrating that this alteration does not occur during tumor = progression. In=20 contrast, the high incidence of IDH1 mutations in A II, O II and = OA II=20 may allow the speculation, that this mutation is involved in early steps = of=20 tumorigenesis. The frequency of mutations in these tumors exceeded the = one=20 observed in GBM. However, IDH1 mutations showed an unbalanced=20 distribution among the different subtypes of GBM. A very high frequency = was=20 observed in secGBM confirming the previous report [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 In contrast, only few prGBM carried IDH1 mutations. This = distribution may=20 even suggest that in those prGBM with IDH1 mutation, the = diagnosis of a=20 previous lower grade astrocytoma has been missed. No mutations were = detected in=20 GS. The analysis of PIAD was of interest because of the observation, that = IDH1 expression was strongly up-regulated in non-functional PIAD=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR7">7</A></CITE>].=20 While IDH1 mutations have been discussed to be of activating = nature=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>],=20 they might also have an effect on transcription or stability of mRNA. = However,=20 analysis of 23 PIAD lacking expression of pituitary hormones revealed no = mutation, suggesting that up-regulated IDH1 expression in these = tumors is=20 independent to the status in the mutational hotspot coding for amino = acid=20 position 132. </DIV> <DIV><A name=3DSec9></A> <DIV class=3DHeading3>Distribution of IDH1, TP53 and EGFR mutations and = of=20 LOH1p/19q in gliomas</DIV> IDH1 mutations did not show any association with TP53 = mutations=20 or LOH1p/19q in A II, A III, O II, O III and mixed OA II and OA III. On = the=20 other hand LOH1p/19q typically is detected in oligodendrogliomas but = rare in=20 astrocytomas and, vice versa, TP53 mutations are frequent in = astrocytomas=20 but rare in oligodendrogliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>].=20 Both alterations are quite frequent in oligoastrocytomas but usually do = not=20 co-occur. Thus, the hallmark molecular findings in these tumors so far=20 segregated between oligodendroglial and astrocytic tumors and this = distribution=20 suggested that these tumors originated from different precursor = populations. In=20 contrast, IDH1 mutations seem to group together A II, A III, O = II, O III,=20 OA II and OA III and suggest a common pathway in their genesis. It might = be that=20 IDH1 mutations occur in the O2A precursor cell giving rise to = astrocytic=20 and oligodendroglial lineage [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR11">11</A></CITE>]=20 and that TP53 mutations and LOH1p/19q arise at a later point in = cells=20 already committed to either lineage. However, such speculation implies = that=20 oligodendroglial tumors arise from precursor cells of oligodendroglia = and this=20 has not yet been demonstrated. With regard to GBM it is of interest that IDH1 mutations are = much more=20 frequent in A II and A III than in prGBM which parallels the = distribution of=20 TP53 mutations in these entities. In contrast, the frequency of = mutations=20 in both, IDH1 and TP53 are high in secGBM as can be = expected from=20 tumors which by definition progress from A II or A III. IDH1 mutations and EGFR amplification were inversely = associated=20 upon pooling all GBM. However, this is to be expected given the high = frequency=20 of IDH1 in secGBM and the well established absence of EGFR = amplification=20 in this subgroup [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR17">17</A></CITE>].=20 Within the prGBM, there was no association between IDH1 and EGFR=20 mutational status. <DIV class=3DPara> <DIV>Mutations of single genes or disruption of signal transduction = pathways=20 have been used to establish models for the molecular subclassification = of=20 gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR17">17</A></CITE>].=20 The addition of the mutational status of IDH1 adds to these = models. For=20 example, the frequency of IDH1 mutations clearly differs between = secGBM=20 and pedGBM both of which are characterized by frequent TP53 = mutations and=20 rare or absent EGFR amplifications. In contrast, = oligodendroglioma,=20 oligoastrocytoma and astrocytoma which so far were on a molecular basis=20 distinguished on their frequency of TP53 mutations and LOH1p/19q = are=20 unified by a high frequency of IDH1 mutations in all three = entities. Data=20 on TP53, combined LOH1p/19q and EGFR from tumors included = in this=20 study have been published previously [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR15">15</A></CITE>]=20 and are compiled in Table <A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#Tab3">3</A>.<A=20 name=3DTab3></A> <DIV class=3DCapt>Table 3 Incidence of=20 mutations in IDH1, TP53 and EGFR and occurrence of = LOH=20 1p/19q in gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR15">15</A></CITE>]=20 </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> </TH> <TH align=3Dleft char=3D"("> IDH1 </TH> <TH align=3Dleft char=3D"("> TP53 </TH> <TH align=3Dleft char=3D"("> LOH 1p/19q</TH> <TH align=3Dleft char=3D"("> EGFRamp </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Glioblastoma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> pedGBM</TD> <TD align=3Dchar char=3D"("> 1/14 (7%)</TD> <TD align=3Dchar char=3D"("> 2/3</TD> <TD align=3Dchar char=3D"("> 0/3</TD> <TD align=3Dchar char=3D"("> 0/2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> prGBM</TD> <TD align=3Dchar char=3D"("> 7/99 (7%)</TD> <TD align=3Dchar char=3D"("> 15/88 (17%)</TD> <TD align=3Dchar char=3D"("> 6/73 (8%)</TD> <TD align=3Dchar char=3D"("> 26/71 (37%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> secGBM</TD> <TD align=3Dchar char=3D"("> 8/8 (88%)</TD> <TD align=3Dchar char=3D"("> 7/8 (88%)</TD> <TD align=3Dchar char=3D"("> 1/8 (13%)</TD> <TD align=3Dchar char=3D"("> 0/8 0(%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> gcGBM</TD> <TD align=3Dchar char=3D"("> 2/8 (25%)</TD> <TD align=3Dchar char=3D"("> 6/7 (86%)</TD> <TD align=3Dchar char=3D"("> 0/6</TD> <TD align=3Dchar char=3D"("> 0/7 (0%)</TD></TR> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Astrocytoma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> A II</TD> <TD align=3Dchar char=3D"("> 33/46 (79%)</TD> <TD align=3Dchar char=3D"("> 13/25 (52%)</TD> <TD align=3Dchar char=3D"("> 6/34 (18%)</TD> <TD align=3Dchar char=3D"("> 0/17 (0%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> A III</TD> <TD align=3Dchar char=3D"("> 29/47 (62%)</TD> <TD align=3Dchar char=3D"("> 13/30 (43%)</TD> <TD align=3Dchar char=3D"("> 5/43 (12%)</TD> <TD align=3Dchar char=3D"("> 1/22 (5%)</TD></TR> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Oligodendroglioma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> O II</TD> <TD align=3Dchar char=3D"("> 36/51 (71%)</TD> <TD align=3Dchar char=3D"("> 3/31 (10%)</TD> <TD align=3Dchar char=3D"("> 30/50 (60%)</TD> <TD align=3Dchar char=3D"("> 0/11 (0%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> O III</TD> <TD align=3Dchar char=3D"("> 36/54 (67%)</TD> <TD align=3Dchar char=3D"("> 4/31 (13%)</TD> <TD align=3Dchar char=3D"("> 35/53 (66%)</TD> <TD align=3Dchar char=3D"("> 0/4</TD></TR> <TR class=3Dnoclass> <TD colSpan=3D5 align=3Dleft> Oligoastrocytoma</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> OA II</TD> <TD align=3Dchar char=3D"("> 36/46 (78%)</TD> <TD align=3Dchar char=3D"("> 6/26 (23%)</TD> <TD align=3Dchar char=3D"("> 24/45 (53%)</TD> <TD align=3Dchar char=3D"("> 0/10 (0%)</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> OA III</TD> <TD align=3Dchar char=3D"("> 29/37 (78%)</TD> <TD align=3Dchar char=3D"("> 6/22 (27%)</TD> <TD align=3Dchar char=3D"("> 26/36 (72%)</TD> <TD align=3Dchar char=3D"("> 0/8 (0%)</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV>Given are the numbers of tumors with mutations among the tumors = examined=20 for this parameter, and in brackets percentages of mutations in this = series=20 </DIV></DIV> <DIV class=3DCaptCont> <DIV>IDH1 Isocitrate dehydrogenase 1, TP53 tumor protein = 53,=20 LOH 1p/19q combined loss of heterozygosity on chromosomal arms 1p = and=20 19q, EGFRamp amplification of the EGFR gene, pedGBM = pediatric glioblastoma WHO grade IV, prGBM primary glioblastoma = WHO grade=20 IV, secGBM secondary glioblastoma WHO grade IV, gcGBM = giant cell=20 glioblastoma WHO grade IV, A II astrocytoma WHO grade II, A = III=20 anaplastic astrocytoma WHO grade III, O II oligodendroglioma WHO = grade=20 II, O III anaplastic oligodendroglioma WHO grade III, OA = II=20 oligoastrocytoma WHO grade II, OA III anaplastic oligoastrocytoma = WHO=20 grade III </DIV></DIV></DIV></DIV></DIV></DIV> <DIV><A name=3DSec10></A> <DIV class=3DHeading3>Association of IDH1 mutations with age</DIV> There was a strong association of age and presence or absence of = IDH1=20 mutations in patients with prGBM. Patients with prGBM and IDH1mut = averaged 40.3 years and those with IDH1wt averaged = 52.6 years=20 (P < 0.005). This confirms previous observations = [<CITE><A=20 href=3D"http://www.springerlink.com/content/r027823071548868/fulltext.htm= l#CR9">9</A></CITE>].=20 Patients with A III and IDH1mut averaged 35.0 years and = those with=20 IDH1wt averaged 44.4 years (P < 0.05). = Patients=20 with O III and IDH1mut averaged 47.7 years and those with=20 IDH1wt averaged 54.8 years (not significant). Patients with = OA III=20 and IDH1mut averaged 44.3 years and those with IDH1wt = averaged 63.5 years (P < 0.0005). The average = ages in=20 patients with A II, O II and OA II did not differ significantly in the = groups=20 with and without IDH1 mutations. An explanation for the association of=20 IDH1 mutations with age only in the highly malignant entities may = be that=20 these tumors sometimes are under-diagnosed due to lack of presence of = necrosis=20 resulting from tumor sampling. Therefore, these entities might contain = some=20 prGBM which do have a low frequency of IDH1 mutations but = predominantly=20 occur in patients of advanced age. Interestingly, no significant = difference is=20 observed in O III which among anaplastic astrocytic and oligodendroglial = tumors=20 poses least problems in differentiating from prGBM. </DIV> <DIV><A name=3DSec11></A> <DIV class=3DHeading3>IDH1 and tumor progression</DIV> IDH1 mutations were frequent in A II (74%) suggesting that = this=20 alteration already is of importance for earlier steps in tumor = formation.=20 Mutations in A III (62%) were somewhat less frequent than in A II, = however, this=20 difference was not significant. IDH1 mutations in secGBM (88%) = were very=20 frequent. In contrast, only few IDH1 mutations were detected in = prGBM=20 (7%). Thus, all tumors belonging to the progression series from A II and = A III=20 to secGBM exhibited IDH1 mutations in a high and comparable = frequency.=20 Similar to A II, O II (71%) and OA II (78%) exhibit a high frequency of=20 IDH1 mutations. Comparable frequencies are observed in O III = (67%) and OA=20 III (78%). These findings suggest that IDH1 mutations are more = likely to=20 be important for tumor formation in diffuse astrocytomas and = oligodendroglial=20 tumors than for progression towards malignancy. The evaluation of a = prognostic=20 and predictive value of IDH1 mutations will require analyses of = large and=20 well-documented trial studies with focus on diffuse gliomas including A = II, A=20 III, O II, O III, OA II and OA III. </DIV> <DIV><A name=3DSec12></A> <DIV class=3DHeading3>Conclusions</DIV> IDH1 mutations typically occur in diffuse gliomas of = astrocytic,=20 oligodendroglial and mixed oligoastroglial differentiation and in = glioblastomas=20 having progressed from these tumors. This is contrasted by the low = frequency of=20 IDH1 mutations in primary glioblastoma. The very high frequency = of=20 IDH1 mutations in WHO grade II astrocytic and oligodendroglial = gliomas=20 suggests a role in early tumor development. </DIV></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments Th= is work=20 was supported by the Bundesministerium f=FCr Bildung und Forschung = (BMBF). We wish=20 to thank K. Lindenberg, U. Ernst and F. 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