Top

Published in:

01-01-2011 | Original Paper

IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group

Authors: Ian F. Pollack, Ronald L. Hamilton, Robert W. Sobol, Marina N. Nikiforova, Maureen A. Lyons-Weiler, William A. LaFramboise, Peter C. Burger, Daniel J. Brat, Marc K. Rosenblum, Emiko J. Holmes, Tianni Zhou, Regina I. Jakacki, for the Children’s Oncology Group

Published in: Child's Nervous System | Issue 1/2011

Abstract

Purpose

Recent studies have demonstrated a high frequency of IDH mutations in adult “secondary” malignant gliomas arising from preexisting lower grade lesions, often in young adults, but not in “primary” gliomas. Because pediatric malignant gliomas share some molecular features with adult secondary gliomas, we questioned whether a subset of these tumors also exhibited IDH mutations.

Experimental design

We examined the frequency of IDH mutations, using real-time polymerase chain reaction and sequencing analysis, in a cohort of 43 pediatric primary malignant gliomas treated on the Children’s Oncology Group ACNS0423 study. The relationship between IDH mutations and other molecular and clinical factors, and outcome, was evaluated.

Results

IDH1 mutations were observed in 7 of 43 (16.3%) tumors; no IDH2 mutations were observed. A striking age association was apparent in that mutations were noted in 7 of 20 tumors (35%) from children ≥14 years, but in 0 of 23 (0%) younger children (p = 0.0024). No association was observed with clinical factors other than age. One-year event-free survival was 86 ± 15% in the IDH-mutated group versus 64 ± 8% in the non-mutated group (p = 0.03, one-sided logrank test). One-year overall survival was 100% in patients with mutations versus 81 ± 6.7% in those without mutations (p = 0.035, one-sided logrank test).

Conclusions

IDH1 mutations are common in malignant gliomas in older children, suggesting that a subset of these lesions may be biologically similar to malignant gliomas arising in younger adults and may be associated with a more favorable prognosis.

Pollack IF (1994) Current concepts: brain tumors in children. N Engl J Med 331:1500–1507CrossRefPubMed

Pollack IF, Hamilton RL, James CD, Finkelstein SD, Burnham J, Yates AJ, Holmes EJ, Zhou T, Finlay JL (2006) Rarity of PTEN deletions and EGFR amplification in malignant gliomas of childhood: results from the Children’s Cancer Group 945 cohort. J Neurosurg Pediatr 105:3431–3437CrossRef

Sung T, Miller DC, Hayes RL, Alonso M, Yee H, Newcomb EW (2000) Preferential inactivation of the p53 tumor suppressor pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol 10:249–259CrossRefPubMed

Bredel M, Pollack IF, Hamilton RL, James CD (1999) Epidermal growth factor receptor (EGFR) expression and gene amplification in high-grade non-brainstem gliomas of childhood. Clin Cancer Res 5:1786–1792PubMed

Cheng Y, Ng H-K, Zhang S-F, Ding M, Pang JC-S, Zheng J, Poon W-S (1999) Genetic alterations in pediatric high-grade astrocytomas. Hum Pathol 30:1284–1290CrossRefPubMed

Raffel C, Frederick L, O’Fallon JR et al (1999) Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. Clin Cancer Res 5:4085–4090PubMed

Sure U, Ruedi D, Tachibana O et al (1997) Determination of p53 mutations, EGFR overexpression, and loss of p16 expression in pediatric glioblastomas. J Neuropathol Exp Neurol 56:782–789PubMed

Pollack IF, Finkelstein SD, Woods J, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Boyett JM, Finlay JL, Sposto R (2002) Expression of p53 and prognosis in malignant gliomas in children. N Engl J Med 346:420–427CrossRefPubMed

Pollack IF, Finkelstein SD, Burnham J, Holmes EJ, Hamilton RL, Yates AJ, Finlay J, Sposto R (2001) Age and TP53 mutation frequency in childhood malignant gliomas. Results in a multi-institutional cohort. Cancer Res 61:7404–7407PubMed

10.

Collins VP (1999) Progression as exemplified by human astrocytic tumors. Semin Cancer Biol 9:267–276CrossRefPubMed

11.

Ichimura K, Bolin MB, Goike HM, Schmidt EE, Moshref A, Collins VP (2000) Deregulation of the p14^ARF/MDM2/p53 pathway is a prerequisite for human astrocytic gliomas with G₁-S transition control gene abnormalities. Cancer Res 60:417–424PubMed

12.

von Deimling A, von Ammon K, Schoenfeld D, Wiestler OD, Seizinger BR, Louis DN (1993) Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19–26CrossRef

13.

Watanabe K, Tachibana O, Sato K, Yonekawa Y, Kleihues P, Ohgaki H (1996) Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6:217–224CrossRefPubMed

14.

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812CrossRefPubMed

15.

Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773CrossRefPubMed

16.

Ichimura K, Pearson DM, Kocialkowski S et al (2009) IDH1 mutations are present in the majority of common adult gliomas but are rare in primary glioblastomas. Neuro-Oncology 11:341–347CrossRefPubMed

17.

Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153CrossRefPubMed

18.

Hartmann C, Meyer J, Balss J et al (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1, 010 diffuse gliomas. Acta Neuropathol 118:469–474CrossRefPubMed

19.

Korshunuv A, Meyer J, Capper D et al (2009) Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytomas from diffuse astrocytomas. Acta Neuropathol 118:401–405CrossRef

20.

Kang MR, Kim MS, Oh JE et al (2009) Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int J Cancer 125:353–355CrossRefPubMed

21.

Bleeker FE, Lamba S, Leenstra S et al (2009) IDH1 mutations at residue p.R132(IDH1(R132)) occur frequently in high-grade gliomas, but not in other solid tumors. Hum Mutat 30:7–11CrossRefPubMed

22.

Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602CrossRefPubMed

23.

Yan H, Bigner DD, Velculescu V, Parsons WD (2009) Mutant metabolic enzymes are at the origin of gliomas. Cancer Res 69:9157–9159CrossRefPubMed

24.

De Carli E, Wang X, Puget S (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:2248CrossRefPubMed

25.

Zhao S, Lin Y, Jiang W et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324:261–265CrossRefPubMed

26.

Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744CrossRefPubMed

27.

Antonelli M, Buttarelli FR, Arcella A et al (2010) Prognostic significance of histological grading, p53 status, YKL-40 expression, and IDH1 mutations in pediatric high-grade gliomas. J Neurooncol. doi:10.1007/s11060-010-0129-5, Published Online: 21 February 2010

28.

Sposto R, Ertel IJ, Jenkin RDT et al (1989) The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Children’s Cancer Study Group. J Neuro-oncol 7:165–177CrossRef

29.

Finlay JL, Boyett JM, Yates AJ et al (1995) Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. J Clin Oncol 13:112–123PubMed

30.

Horbinski C, Kofler J, Kelly L, Murdoch GH, Nikiforova MN (2009) The diagnostic utility of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed paraffin-embedded glioma tissues. J Neuropathol Exp Neurol 68:1319–1325CrossRefPubMed

31.

Shi SR, Key ME, Kalra KL (1991) Antigen retrieval in formalin-fixed, paraffin embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem 39:741–748PubMed

32.

Vojtesek B, Bartek J, Midgley CA, Lane DP (1992) An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. J Immunol Methods 151:237–244CrossRefPubMed

33.

Hsu S, Raine L, Fanger H et al (1981) Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques. J Histochem Cytochem 29:577–580PubMed

34.

Pollack IF, Boyett JM, Yates AJ, Burger PC, Gilles FH, Davis RL, Finlay JL (2003) The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience. Neuro-Oncology 5:197–207CrossRefPubMed

35.

Kleihues P, Burger PC, Scheithauer BW (1993) Histological typing of tumours of the central nervous system. In: Sobin LH (ed) International histological classification of tumours, vol 21, 2nd edn. Springer-Verlag, Geneva, pp 11–16

36.

Kalbfleisch JD, Prentice RI (1980) The statistical analysis of failure time data. John Wiley and Sons, New York, pp 163–180

37.

Dixon WJ, Massey FJ (1969) Introduction to statistical analysis, 3rd edn. McGraw-Hill, New York

Title: IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group
Authors: Ian F. Pollack
Ronald L. Hamilton
Robert W. Sobol
Marina N. Nikiforova
Maureen A. Lyons-Weiler
William A. LaFramboise
Peter C. Burger
Daniel J. Brat
Marc K. Rosenblum
Emiko J. Holmes
Tianni Zhou
Regina I. Jakacki
for the Children’s Oncology Group
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Child's Nervous System / Issue 1/2011
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-010-1264-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children’s Oncology Group

Abstract

Purpose

Experimental design

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Experimental design

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2011

ASPM gene expression in medulloblastoma

Gliomatosis cerebri in young patients' report of three cases and review of the literature

Spinal low-grade neoplasm with leptomeningeal dissemination mimicking tuberculous meningitis in a child

Polycomb genes expression as a predictor of poor clinical outcome in children with medulloblastoma

Huge hydrocephalus: definition, management, and complications

“Groans less, seems more comfortable:” Harvey Cushing's redefinition of success in the operative treatment of pediatric intracranial lesions