Bailey S

Clifford SC

Ellison DW

Fruhwald MC

Hasselblatt M

Hayden JT

Newcastle University E-Prints

[Cell Cycle 8:11, 1806-1807; 1 June 2009]; ©2009 Landes Bioscience1806 Cell Cycle 2009; Vol. 8 Issue 11Supratentorial primitive neuroectodermal tumors (sPNET) are rare aggressive embryonal tumors of the cerebral hemispheres, which predominantly occur in childhood but also arise in adults. Despite multi-modal therapy, less than half of affected patients will survive 5 years post-diagnosis, and late effects associated with current treatment protocols are a significant complication in survivors.1 Advances in our understanding of the molecular basis of sPNET development will be critical to improve outcome. The biological mechanisms underlying sPNET pathogenesis, however, remain poorly understood and afford few opportunities for the application of novel or targeted therapeutic approaches to achieve this objective.In a recently published systematic screen of 22 glioblastoma tumor samples for evidence of genetic mutation in 20,661 protein coding genes, the most frequently mutated novel candidate cancer gene was IDH1, which encodes cytoplasmic isocitrate dehydrogenase, involved in the control of cellular oxidative damage.2 Subsequent mutation analysis in an extensive panel identified IDH1 mutations in 12% (18/149) of glioblastomas.A series of studies have now investigated IDH1 mutations in human malignancies,2-6 the combined results of which are summarised in Table 1. Analysis of central nervous system (CNS) tumors identified IDH1 mutations in 37% of cases (590 mutations, 1,603 cases), all affecting codon 132. IDH1 mutations appear to occur predominantly in neuroepithelial tumors of glial origin. In embryonal brain tumors, no evidence of IDH1 mutation has been found in the infratentorial PNET, medulloblastoma (0/113), however mutations were identified in a third (3/9) of sPNET. In contrast, no IDH1 mutations were detected in a panel of 1,053 extracranial tumors. Taken together, these data indicate that IDH1 mutations are a common and specific feature of glioblastomas and other brain tumors of neuroepithelial and in particular glial origin, and suggest a potential role in the pathogenesis of sPNET.We therefore investigated the prevalence of IDH1 mutations in an extensive cohort of sPNET, which included 34 primary tumors (mean age 9.4 years; range 2 months to 30 years; 8 infant cases <3 years, 20 childhood cases ≥3 years to 17 years, 6 adult cases ≥18 years). Polymerase chain reaction (PCR) was employed to amplify exon 4 of IDH1, using previously described primers and methods.5 PCR products were subsequently purified (PureLinkTM PCR Purification kit, Invitrogen, Paisley, UK) and directly sequenced in forward and reverse directions using an Applied Biosystems 3730 DNA Analyser (DBS Genomics, Durham University, UK).Mutations in IDH1 were identified in 2/34 (6%) primary sPNET. In both cases, a missense mutation in codon 132 was observed (G395A; R132H). Interestingly, both mutations were detected in sPNET from adult cases (2/6; ≥18 years at diagnosis), while no muta-tions were observed in paediatric sPNET (0/28; 0–17 years) (p = 0.027; Fisher’s exact test). This overall rate of IDH1 mutation in sPNET is lower than previously reported (33% (3/9) of cases; Balss et al.5). However, detailed examination of the ages at diagnosis of cases in this previous study revealed the two datasets are in close agreement; IDH1 Letter to the EditorFrequent IDH1 mutations in supratentorial primitive  neuroectodermal tumors (sPNET) of adults but not childrenJames T. Hayden,1 Michael C. Frühwald,2 Martin Hasselblatt,3 David W. Ellison,4 Simon Bailey1 and Steven C. Clifford1,*1Northern Institute for Cancer Research; The Medical School; Newcastle University; Newcastle upon Tyne, UK; 2Department of Pediatric Hematology; Oncology; University Children’s Hospital; Münster, Germany; 3Institute of Neuropathology; University Hospital Münster; Münster, Germany; and 4Department of Pathology; St. Jude Children’s Research Hospital; Memphis, TN USAKey words: IDH1, mutation, supratentorial, PNET, sPNET*Correspondence to: Steven C. Clifford; Northern Institute for Cancer Research; The Medical School; Framlington Place; Newcastle University; Newcastle-upon-Tyne NE2 4HH UK; Tel.: +44.191.2464422; Fax: +44.191.2464301; Email: s.c.clifford@ncl.ac.ukSubmitted: 03/23/09; Accepted: 03/30/09Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/8594Table 1  Reported isocitrate dehydrogenase (IDH1) mutations in clinically classified human tumor biopsies Number of Number Mutation Reference  tumors of Frequency  analyzed mutations (%)Central nervous system (CNS)Astrocytic Tumors 917 307 33 2–6Oligodendroglial Tumors 241 182 76 3–6Oligoastrocytic Tumors 124 101 81 4–6Embryonal Tumors   sPNET 9 3 33 5   Medulloblastoma 113 0 0 5, 6Ependymal Tumors 87 0 0 4–6Sellar Region Tumor 23 0 0 5Cranial & Paraspinal 17 0 0 5 Nerves TumorsMeningothelial Cell Tumors 72 0 0 5Non-CNSLeukamia 63 0 0 6Bladder 34 0 0 3Breast 223 0 0 3, 6Gastric 57 0 0 6Colorectal 267 0 0 3, 6Lung 142 0 0 3, 6Melanoma 23 0 0 3Thyroid 42 0 0 3Ovary 73 0 0 3, 6Pancreas 118 0 0 3, 6Prostate 11 0 0 3, 6IDH1 mutations in sPNETwww.landesbioscience.com Cell Cycle 1807mutations also occurred exclusively in adult sPNET in the study by Balss et al.5 (3/6 ≥18 years; 0/3 <18 years) (Prof. A. von Deimling, Personal communication). Taken together, these data clearly demon-strate that mutations in IDH1 are amongst the most frequent mutational events identified in sPNET to date, and characterize a significant proportion of adult cases (42% (5/12), based on the combined data-sets), but do not appear to play a major role in paediatric cases (0/31 in combination; p = 0.0008, Fisher’s exact test).It is notable that, in studies to date, IDH1 mutations occur specifi-cally in CNS malignancies and, within these, have only been detected in astrocytic, oligodendroglial, oligoastrocytic and adult sPNET, suggesting IDH1 plays a role in the development of these tumors, but not in other brain tumor types including medulloblastomas. Moreover, our findings are consistent with the arguments that (i) PNET arising in the infratentorial (i.e., medulloblastoma) and supratentorial (i.e., sPNET) compartments display distinct mechanisms of molecular patho-genesis, despite their histopathological similarities, and (ii) sPNET arising in adults and children differ at the molecular level. However, whilst the identification of IDH1 mutations in sPNET and other neuroepithelial tumors suggests these tumor types may share common mechanisms of molecular pathogenesis, it must also be considered that the observation of IDH1 mutations in both may reflect the recognized challenge that can exist in establishing the histopathological differen-tial diagnosis of these different supratentorial tumor types.7In conclusion, these data identify IDH1 mutations as a feature of a significant subset of adult sPNET. The significance of IDH1 mutations in this group, and any functional contribution they make to tumor development is, however, currently unclear. Further studies are now required to investigate the role of IDH1 mutations in tumorigenesis, their relationship to disease histopathology, and to discover whether these findings may be exploited to aid the development of improved therapeutic approaches for patients with sPNET.AcknowledgementsThis work was supported by grants from the Samantha Dickson Brain Tumor Trust (SDBTT), the North of England Children’s Cancer Research Fund (NECCR), and Cancer and Leukaemia in Children (CLIC).References 1. Pizer BL, et al. Eur J Cancer 2006; 42:1120-8. 2. Parsons DW, et al. Science 2008; 321:1807-12. 3. Bleeker FE, et al. Hum Mutat 2009; 30:7-11. 4. Watanabe T, et al. Am J Path 2009; 174:(epub). 5. Balss J, et al. Acta Neuropathol 2008; 116:597-602. 6. Yan H, et al. New Eng J Med 2009; 360:765-73. 7. Armstrong DD, et al. Brain Pathol 2003; 13:373-5.

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Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children

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Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children

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