Immunohistochemical expression of IDH1R132H in Astrocytic tumours and its association with histopathological grade, TP53 and EGFR protein expression
Keywords:
IDH, glioma, EGFR, TP53, immunohistochemistry, genotype
Abstract
Background: Molecular studies have uncovered that histopathologically diagnosed Astrocytomas are genetically heterogeneous. Majority of Diffuse Astrocytomas (DA), Anaplastic Astrocytomas (AA) and secondary Glioblastoma multiforme (GBM) have concurrent mutations of IDH, TP53 and ATRX. Astrocytomas without IDH mutation have distinct genotype and poor prognosis. Primary GBM show EGFR amplification and lack IDH mutation.Methods: We studied 95 Astrocytic tumors including 15 Pilocytic Astrocytoma (PA), 21 Diffuse astrocytomas, 7 Anaplastic astrocytomas and 52 GBM using tissue-microarray (TMA) to assess immunohistochemical expression of IDH1R132H, TP53 and EGFR protein in all four grades and the association between these three immunohistochemical markers. TMA blocks with core size 3.0 mm were constructed using manual tissue-microarrayer. IHC for IDH1R132H, TP53 and EGFR was performed.Results: 13%(2/15) of PA showed IDH1R132H expression. TP53 and EGFR expression was not seen in any case. 52%(11/21), 71%(15/21) and 9%(2/21) of DA showed expression of IDH1, TP53 and EGFR respectively. Frequency of mutant IDH1, TP53 and EGFR in Anaplastic astrocytoma was 85%(6/7), 85%(6/7) and 0%(0/7). Among GBMs there was significant difference in IHC expression of IDH1 and EGFR. Primary GBMs show high EGFR expression of 70%(26/37) and low IDH1 expression of 21%(8/37). Secondary GBM in contrast show higher IDH1 expression 80%(12/15) and low EGFR expression of 13%(2/15).Conclusion: IDH and TP53 mutations are seen in majority of DA, AA and secondary GBM and are hallmarks of these tumors. Primary GBMs have distinct molecular pathway. They lack IDH, TP53 mutation and overexpress EGFR.DOI:10.21276/APALM.1458References
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13. Liu X-Y, Gerges N, Korshunov A, Sabha N, Khuong-Quang D-A, Fontebasso AM, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumours carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol. 2012;124(5):615–25.
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16. Ichimura K, Pearson DM, Kocialkowski S, Bäcklund LM, Chan R, Jones DTW, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol [Internet]. Oxford University Press; 2009;11(4):341–7.
17. Muller PAJ, Vousden KH. p53 mutations in cancer. Nat Cell Biol. Nature Research; 2013;15(1):2–8.
18. Louis DN. The p53 gene and protein in human brain tumours. J Neuropathol Exp Neurol. 1994;53(1):11–21.
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20. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumourigenicity. Proc Natl Acad Sci U S A. 1994;91(16):7727–31.
21. Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst. 2001;93(16):1246–56.
22. Hatanpaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. Neoplasia Press; 2010;12(9):675–84.
23. Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996;6(3):217-23-4.
24. Popovici-Muller J, Saunders JO, Salituro FG, Travins JM, Yan S, Zhao F, et al. Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumour 2-HG in Vivo. ACS Med Chem Lett. American Chemical Society; 2012;3(10):850–5.
25. Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. Wiley-Blackwell; 2014;6(11):1359–70. FIGURES WITH LEG
2. IARC Publications Website - WHO Classification of Tumours of the Central Nervous System [Internet]. Available from: http://publications.iarc.fr/Book-And-Report-Series/Who-Iarc-Classification-Of-Tumours/Who-Classification-Of-Tumours-Of-The-Central-Nervous-System-2016
3. Ichimura K, Ohgaki H, Kleihues P, Collins VP. Molecular pathogenesis of astrocytic tumours. J Neurooncol. 2004;70(2):137–60.
4. Ohgaki H, Kleihues P. The Definition of Primary and Secondary Glioblastoma. Clin Cancer Res. 2013;19(4):764–72.
5. Huang PH, Xu AM, White FM. Oncogenic EGFR signaling networks in glioma. Sci Signal. 2009;2(87):re6.
6. Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumours. Clin Cancer Res. 2003;9(11):4247–54.
7. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53.
8. Kim SY, Park J-W. Cellular defense against singlet oxygen-induced oxidative damage by cytosolic NADP+-dependent isocitrate dehydrogenase. Free Radic Res. 2003;37(3):309–16.
9. Lee SM, Koh H-J, Park D-C, Song BJ, Huh T-L, Park J-W. Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells. Free Radic Biol Med. 2002;32(11):1185–96.
10. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. NIH Public Access; 2009;360(8):765–73.
11. Bleeker FE, Atai NA, Lamba S, Ard J, Rijkeboer D, et al. The prognostic IDH1 R132 mutation is associated with reduced NADP + -dependent IDH activity in glioblastoma.
12. Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. NIH Public Access; 2009;324(5924):261–5.
13. Liu X-Y, Gerges N, Korshunov A, Sabha N, Khuong-Quang D-A, Fontebasso AM, et al. Frequent ATRX mutations and loss of expression in adult diffuse astrocytic tumours carrying IDH1/IDH2 and TP53 mutations. Acta Neuropathol. 2012;124(5):615–25.
14. Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas. Clin Cancer Res. 2009;15(19).
15. Ohgaki H, Kleihues P. Genetic Pathways to Primary and Secondary Glioblastoma. Am J Pathol. 2007;170(5):1445–53.
16. Ichimura K, Pearson DM, Kocialkowski S, Bäcklund LM, Chan R, Jones DTW, et al. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol [Internet]. Oxford University Press; 2009;11(4):341–7.
17. Muller PAJ, Vousden KH. p53 mutations in cancer. Nat Cell Biol. Nature Research; 2013;15(1):2–8.
18. Louis DN. The p53 gene and protein in human brain tumours. J Neuropathol Exp Neurol. 1994;53(1):11–21.
19. Bourdon JC, Laurenzi V De, Melino G, Lane D. p53: 25 years of research and more questions to answer. Cell Death Differ. Nature Publishing Group; 2003;10(4):397–9.
20. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumourigenicity. Proc Natl Acad Sci U S A. 1994;91(16):7727–31.
21. Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst. 2001;93(16):1246–56.
22. Hatanpaa KJ, Burma S, Zhao D, Habib AA. Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. Neoplasia Press; 2010;12(9):675–84.
23. Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol. 1996;6(3):217-23-4.
24. Popovici-Muller J, Saunders JO, Salituro FG, Travins JM, Yan S, Zhao F, et al. Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumour 2-HG in Vivo. ACS Med Chem Lett. American Chemical Society; 2012;3(10):850–5.
25. Carlsson SK, Brothers SP, Wahlestedt C. Emerging treatment strategies for glioblastoma multiforme. EMBO Mol Med. Wiley-Blackwell; 2014;6(11):1359–70. FIGURES WITH LEG
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2017-10-27
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