Mutations in IDH1/2 Genes Predict Better Disease Outcome of Glioma Patients-A Study From Western India
Abstract
Introduction: Isocitrate Dehydrogenase (IDH) plays an important role in cellular metabolism. In gliomas, the mutational status of IDH1/2 genes have paramount significance, however, study from Western India is limited. Therefore, in the current study, we sought to explore the clinical impact of IDH1/2 mutations on glioma patients from Western India. Materials and Method: A total of 50 pre-therapeutic, histopathologically confirmed patients with astrocytoma tumors were included and IDH1/2 mutations were detected using real-time PCR. IDH1/2 mutations were correlated with clinicopathological parameters and disease outcomes. Data were evaluated by SPSS software. Results: The overall incidence of IDH1/2 mutations was noted in 24% (12/50) of glioma patients. Out of 12 patients whose tumors showed IDH mutations, 83% of patients have IDH1 mutations, whereas 17% showed IDH2 mutation. Further, in IDH1 mutations, IDH1 R132H & IDH1 R132C mutations were noted in, 80% and 20% of patients, respectively. When correlated with clinicopathological parameters, a significant inverse correlation was found with patients' age (χ2= 9.75, r = -0.476, p=0.001) and grade of tumors (χ2=17.51, r =-0.636, p=0.0001). In Kaplan-Meier survival analysis, apart from age (Log rank=5.443, p=0.020), IDH mutation status (Log rank=3.855, p=0.050), and both, IDH mutation and low-grade glioma tumors (Log rank=6.492, p=0.039) remained significant parameters for predicting better 24 months PFS and OS of glioma patients. However, in multivariate survival analysis using the Cox Proportional Hazard Forward Stepwise Model, only a combination of low-grade glioma with the presence of IDH mutation emerged at step one as a positive significant independent prognostic factor that predict better PFS (HR=2.92, 95% CI=1.12-7.61, p=0.028) and OS (HR=3.0, 95% CI=1.45-6.19, p=0.003). Conclusion: Based on this data, we concluded that for glioma patients, apart from patients' age, low-grade tumors with the presence of IDH mutations remained significant independent positive prognosticators and would be helpful to clinicians for better management of glioma patients.
1. Patel AP, Fisher JL, Nichols E, Abd-Allah F, Abdela J, Abdelalim A, Abraha HN, Agius D, Alahdab F, Alam T, Allen CA. Global, regional, and national burden of brain and other CNS cancer, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2019 Apr 1;18(4):376-93.
2. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clinical cancer research. 2012 Oct 15;18(20):5562-71.
3. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. Journal of the National Cancer Institute. 2010 Jul 7;102(13):932-41.
4. Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discovery medicine. 2016 May 23;21(117):373-80.
5. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012 Mar 22;483(7390):474-8.
6. Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010 Dec;29(49):6409-17.
7. Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends in molecular medicine. 2010 Sep 1;16(9):387-97.
8. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009 Dec 10;462(7274):739-44.
9. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer cell. 2011 Jan 18;19(1):17-30.
10. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell. 2010 Dec 14;18(6):553-67.
11. Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL, Weinstock DM, Sharp KA, Thompson CB. Identification of additional IDH mutations associated with oncometabolite R (−)-2-hydroxyglutarate production. Oncogene. 2012 May;31(19):2491-8.
12. Catteau A, Girardi H, Monville F, Poggionovo C, Carpentier S, Frayssinet V, Voss J, Jenkins R, Boisselier B, Mokhtari K, Sanson M. A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma. Acta Neuropathologica Communications. 2014 Dec;2(1):1-2.
13. Kandalgaonkar P, Sahu A, Saju AC, Joshi A, Mahajan A, Thakur M, Sahay A, Epari S, Sinha S, Dasgupta A, Chatterjee A. Predicting IDH subtype of grade 4 astrocytoma and glioblastoma from tumor radiomic patterns extracted from multiparametric magnetic resonance images using a machine learning approach. Frontiers in Oncology. 2022:5247.
14. Ranjan Das B, Tangri R, Ahmad F, Roy A, Patole K. Molecular investigation of isocitrate dehydrogenase gene (IDH) mutations in gliomas: first report of IDH2 mutations in Indian patients. Asian Pacific Journal of Cancer Prevention. 2013;14(12):7261-4.
15. Ichimura K, Pearson DM, Kocialkowski S, Bäcklund LM, Chan R, Jones DT, Collins VP. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-oncology. 2009 Aug 1;11(4):341-7.
16. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. The American journal of pathology. 2009 Apr 1;174(4):1149-53.
17. Zou P, Xu H, Chen P, Yan Q, Zhao L, Zhao P, Gu A. IDH1/IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PloS one. 2013 Jul 22;8(7):e68782
18. Chatterjee D, Radotra BD, Kumar N, Vasishta RK, Gupta SK. IDH1, ATRX, and BRAFV600E mutation in astrocytic tumors and their significance in patient outcome in north Indian population. Surgical neurology international. 2018;9.
19. Jha P, Suri V, Sharma V, Singh G, Sharma MC, Pathak P, Chosdol K, Jha P, Suri A, Mahapatra AK, Kale SS. IDH1 mutations in gliomas: first series from a tertiary care centre in India with comprehensive review of literature. Experimental and molecular pathology. 2011 Aug 1;91(1):385-93.
20. Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A, Rodolfo M. IDH1 mutations at residue p. R132 (IDH1R132) occur frequently in high‐grade gliomas but not in other solid tumors. Human mutation. 2009 Jan;30(1):7-11.
21. Felsberg J, Wolter M, Seul H, Friedensdorf B, Göppert M, Sabel MC, Reifenberger G. Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing. Acta neuropathologica. 2010 Apr;119:501-7.
22. Uno M, Oba-Shinjo SM, Silva RD, Miura F, Clara CA, Almeida JR, Malheiros SM, Bianco AM, Brandt R, Ribas GC, Feres H. IDH1 mutations in a Brazilian series of Glioblastoma. Clinics. 2011;66:163-5.
23. Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. Journal of Neuropathology & Experimental Neurology. 2009 Dec 1;68(12):1319-25.
24. Mukasa A, Takayanagi S, Saito K, Shibahara J, Tabei Y, Furuya K, Ide T, Narita Y, Nishikawa R, Ueki K, Saito N. Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients. Cancer science. 2012 Mar;103(3):587-92.
25. Sarma S, Khonglah Y, Mishra J, Kakati A, Phukan P. Gliomas-An experience based on molecular markers. Journal of Family Medicine and Primary Care. 2021 Mar;10(3):1341.
26. Kaspar JW, Niture SK, Jaiswal AK. Nrf2: INrf2 (Keap1) signaling in oxidative stress. Free Radical Biology and Medicine. 2009 Nov 1;47(9):1304-9.
27. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H. IDH1 and IDH2 mutations in gliomas. New England journal of medicine. 2009 Feb 19; 360(8):765-73.
28. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M. 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 neuropathologica. 2009 Oct;118:469-74
29. Agarwal S, Sharma MC, Jha P, Pathak P, Suri V, Sarkar C, Chosdol K, Suri A, Kale SS, Mahapatra AK, Jha P. Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing. Neuro-oncology. 2013 Jun 1;15(6):718-26.
30. Xia L, Wu B, Fu Z, Feng F, Qiao E, Li Q, Sun C, Ge M. Prognostic role of IDH mutations in gliomas: a meta-analysis of 55 observational studies. Oncotarget. 2015 Jul 7;6(19):17354.
31. Mohrenz IV, Antonietti P, Pusch S, Capper D, Balss J, Voigt S, Weissert S, Mukrowsky A, Frank J, Senft C, Seifert V. Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis. 2013 Nov;18:1416-25.
32. Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, Selfridge J, Zurayk M, Lou JJ, Everson RG, Wu KC. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro-oncology. 2013 Jan 1;15(1):57-68.
33. Jin G, Reitman ZJ, Spasojevic I, Batinic-Haberle I, Yang J, Schmidt-Kittler O, Bigner DD, Yan H. 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP+-dependent isocitrate dehydrogenase mutations. PloS one. 2011 Feb 4;6(2):e16812.
34. Deng L, Xiong P, Luo Y, Bu X, Qian S, Zhong W, Lv S. Association between IDH1/2 mutations and brain glioma grade. Oncology letters. 2018 Oct 1;16(4):5405-9.
35. Murugan AK, Alzahrani AS. Isocitrate dehydrogenase IDH1 and IDH2 mutations in human cancer: Prognostic implications for gliomas. British Journal of Biomedical Science. 2022:8.
2. Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clinical cancer research. 2012 Oct 15;18(20):5562-71.
3. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. Journal of the National Cancer Institute. 2010 Jul 7;102(13):932-41.
4. Fujii T, Khawaja MR, DiNardo CD, Atkins JT, Janku F. Targeting isocitrate dehydrogenase (IDH) in cancer. Discovery medicine. 2016 May 23;21(117):373-80.
5. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012 Mar 22;483(7390):474-8.
6. Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010 Dec;29(49):6409-17.
7. Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends in molecular medicine. 2010 Sep 1;16(9):387-97.
8. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009 Dec 10;462(7274):739-44.
9. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer cell. 2011 Jan 18;19(1):17-30.
10. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell. 2010 Dec 14;18(6):553-67.
11. Ward PS, Cross JR, Lu C, Weigert O, Abel-Wahab O, Levine RL, Weinstock DM, Sharp KA, Thompson CB. Identification of additional IDH mutations associated with oncometabolite R (−)-2-hydroxyglutarate production. Oncogene. 2012 May;31(19):2491-8.
12. Catteau A, Girardi H, Monville F, Poggionovo C, Carpentier S, Frayssinet V, Voss J, Jenkins R, Boisselier B, Mokhtari K, Sanson M. A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma. Acta Neuropathologica Communications. 2014 Dec;2(1):1-2.
13. Kandalgaonkar P, Sahu A, Saju AC, Joshi A, Mahajan A, Thakur M, Sahay A, Epari S, Sinha S, Dasgupta A, Chatterjee A. Predicting IDH subtype of grade 4 astrocytoma and glioblastoma from tumor radiomic patterns extracted from multiparametric magnetic resonance images using a machine learning approach. Frontiers in Oncology. 2022:5247.
14. Ranjan Das B, Tangri R, Ahmad F, Roy A, Patole K. Molecular investigation of isocitrate dehydrogenase gene (IDH) mutations in gliomas: first report of IDH2 mutations in Indian patients. Asian Pacific Journal of Cancer Prevention. 2013;14(12):7261-4.
15. Ichimura K, Pearson DM, Kocialkowski S, Bäcklund LM, Chan R, Jones DT, Collins VP. IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. Neuro-oncology. 2009 Aug 1;11(4):341-7.
16. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. The American journal of pathology. 2009 Apr 1;174(4):1149-53.
17. Zou P, Xu H, Chen P, Yan Q, Zhao L, Zhao P, Gu A. IDH1/IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PloS one. 2013 Jul 22;8(7):e68782
18. Chatterjee D, Radotra BD, Kumar N, Vasishta RK, Gupta SK. IDH1, ATRX, and BRAFV600E mutation in astrocytic tumors and their significance in patient outcome in north Indian population. Surgical neurology international. 2018;9.
19. Jha P, Suri V, Sharma V, Singh G, Sharma MC, Pathak P, Chosdol K, Jha P, Suri A, Mahapatra AK, Kale SS. IDH1 mutations in gliomas: first series from a tertiary care centre in India with comprehensive review of literature. Experimental and molecular pathology. 2011 Aug 1;91(1):385-93.
20. Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A, Rodolfo M. IDH1 mutations at residue p. R132 (IDH1R132) occur frequently in high‐grade gliomas but not in other solid tumors. Human mutation. 2009 Jan;30(1):7-11.
21. Felsberg J, Wolter M, Seul H, Friedensdorf B, Göppert M, Sabel MC, Reifenberger G. Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing. Acta neuropathologica. 2010 Apr;119:501-7.
22. Uno M, Oba-Shinjo SM, Silva RD, Miura F, Clara CA, Almeida JR, Malheiros SM, Bianco AM, Brandt R, Ribas GC, Feres H. IDH1 mutations in a Brazilian series of Glioblastoma. Clinics. 2011;66:163-5.
23. Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. Journal of Neuropathology & Experimental Neurology. 2009 Dec 1;68(12):1319-25.
24. Mukasa A, Takayanagi S, Saito K, Shibahara J, Tabei Y, Furuya K, Ide T, Narita Y, Nishikawa R, Ueki K, Saito N. Significance of IDH mutations varies with tumor histology, grade, and genetics in Japanese glioma patients. Cancer science. 2012 Mar;103(3):587-92.
25. Sarma S, Khonglah Y, Mishra J, Kakati A, Phukan P. Gliomas-An experience based on molecular markers. Journal of Family Medicine and Primary Care. 2021 Mar;10(3):1341.
26. Kaspar JW, Niture SK, Jaiswal AK. Nrf2: INrf2 (Keap1) signaling in oxidative stress. Free Radical Biology and Medicine. 2009 Nov 1;47(9):1304-9.
27. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H. IDH1 and IDH2 mutations in gliomas. New England journal of medicine. 2009 Feb 19; 360(8):765-73.
28. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M. 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 neuropathologica. 2009 Oct;118:469-74
29. Agarwal S, Sharma MC, Jha P, Pathak P, Suri V, Sarkar C, Chosdol K, Suri A, Kale SS, Mahapatra AK, Jha P. Comparative study of IDH1 mutations in gliomas by immunohistochemistry and DNA sequencing. Neuro-oncology. 2013 Jun 1;15(6):718-26.
30. Xia L, Wu B, Fu Z, Feng F, Qiao E, Li Q, Sun C, Ge M. Prognostic role of IDH mutations in gliomas: a meta-analysis of 55 observational studies. Oncotarget. 2015 Jul 7;6(19):17354.
31. Mohrenz IV, Antonietti P, Pusch S, Capper D, Balss J, Voigt S, Weissert S, Mukrowsky A, Frank J, Senft C, Seifert V. Isocitrate dehydrogenase 1 mutant R132H sensitizes glioma cells to BCNU-induced oxidative stress and cell death. Apoptosis. 2013 Nov;18:1416-25.
32. Li S, Chou AP, Chen W, Chen R, Deng Y, Phillips HS, Selfridge J, Zurayk M, Lou JJ, Everson RG, Wu KC. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro-oncology. 2013 Jan 1;15(1):57-68.
33. Jin G, Reitman ZJ, Spasojevic I, Batinic-Haberle I, Yang J, Schmidt-Kittler O, Bigner DD, Yan H. 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP+-dependent isocitrate dehydrogenase mutations. PloS one. 2011 Feb 4;6(2):e16812.
34. Deng L, Xiong P, Luo Y, Bu X, Qian S, Zhong W, Lv S. Association between IDH1/2 mutations and brain glioma grade. Oncology letters. 2018 Oct 1;16(4):5405-9.
35. Murugan AK, Alzahrani AS. Isocitrate dehydrogenase IDH1 and IDH2 mutations in human cancer: Prognostic implications for gliomas. British Journal of Biomedical Science. 2022:8.
| Files | ||
| Issue | Vol 14 No 4 (2022) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/bccr.v14i4.14674 | |
| Keywords | ||
| Glioma IDH Univariate survival analysis Multivariate analysis PFS OS | ||
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How to Cite
1.
Gohil N, Bhalala N, Mistry M, Trivedi T. Mutations in IDH1/2 Genes Predict Better Disease Outcome of Glioma Patients-A Study From Western India. Basic Clin Cancer Res. 2023;14(4):202-212.
