Immunohistochemical analysis of IDH1, ATRX, p53, and Ki-67 in glioblastoma and diffuse infiltrative glioma: therapeutic and prognostic correlation
Abstract
Background/Aim. The most common molecular alterations in high-grade astrocytoma include mutation of the isocitrate dehydrogenase (IDH) gene, loss of 1p19q, and p53 mutation. The aim of the study was to determine the prevalence of high-grade astrocytoma and glioblastoma and to examine the immunohistochemical staining patterns of IDH1, alpha-thalassemia/mental retardation X-linked (ATRX), p53, and Ki-67, as well as neoplastic morphological findings, treatment response, and effects on prognosis. Methods. Patients with IDH-mutant or IDH-wild-type glial tumors diagnosed at our center between January 2016 and January 2022 were included in the study. Patients were divided into groups according to age as follows: 7–40, 41–55, 56–64, and ≥ 65 years. The impact of demographic and clinical features on survival was analyzed. The effects of IDH1, p53, ATRX, and Ki-67 parameters on treatment success and prognosis were investigated. The Chi-square test was used to compare independent categorical variables, while the McNemar test was used for dependent categorical variables between the groups. Kaplan-Meier method and Cox proportional regression model (forward model) were used to estimate the mean and median survival times, failure rates, and hazard ratios. Results. In the study, 115 (56.1%) patients were male and 90 (43.9%) were female. The patients ranged in age from 7 to 84 years. There was no significant relationship between gender and age groups on survival (p = 0.113). However, there was a significant association between the glioblastoma grade and survival (p = 0.024). There were 65 (31.7%) patients who died. The mean overall survival of all patients was 45.2 months (median: 24 months). While 45 (21.2%) patients were found to have IDH1 mutation, the number of patients negative for the mutation was 160 (78.8%). Overall survival was significantly longer in IDH1-positive patients (mean: 65.8, median: 80) than in IDH1-negative patients (mean: 25.7, median: 22) (p = 0.019). Conclusion. It was found that mutations of IDH1 and ATRX and overexpression of p53 alone significantly impacted the prognosis of glioblastoma patients. However, radiotherapy and chemotherapy had a positive effect on patient survival. Survival can be increased by adding additional treatments to patients with ATRX mutations.
References
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classi-fication of Tumours of Central Nervous System. 4th ed. Lyon: IARC Press, 2007. p. 312.
Montgomery RM, Queiroz LS, Rogerio F. EGFR, p53, IDH-1 and MDM2 immunohistochemical analysis in glioblastoma: therapeutic and prognostic correlation. Arq Neuropsiquiatr 2015; 73(7): 561–8.
Pekmezci M, Söylemezoğlu F, Öngürü Ö, Öz B, Tihan T. World Health Organization Grade II and III Diffuse Gliomas in Adults. Türkiye Кlinikleri J Med Pathol – Special Topics 2016; 1(2): 1–9. (Turkish)
Gülten G, Yalçın N, Baltalarlı B, Doğu G, Acar F, Doğruel Y. The importance of IDH1, ATRX, and WT1 mutations in glio-blastoma. Pol J Pathol 2020; 71(2): 127–37.
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classi-fication of Tumours of Central Nervous System. Revised 4th ed. Lyon: IARC, 2016. p. 408.
Weller M, Weber RG, Willscher E, Riehmer V, Hentschel B, Kreuz M, et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol 2015; 129(5): 679–93.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organi-zation classification of tumours of the central nervous system: a summary. Acta Neuropathol 2016; 131(6): 803–20.
WHO Classification of Tumours Editorial Board. World Health Organization Classification of Tumours: Central Nervous Sys-tem Tumours. 5th ed. Lyon: WHO; 2021. pp. 15–39.
Reitman ZJ, Yan H. Izocitrate dehydrogenase 1 and 2 muta-tions in cancer: alterations at a crossroads of cellular metabo-lism. J Natl Cancer Inst 2010; 102(13): 932–41.
Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 muta-tions are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 2009; 174(4): 1149–53.
Karsy M, Guan J, Cohen AL, Jensen RL, Colman H. New molec-ular considerations for glioma: IDH, ATRX, BRAF, TERT, H3 K27M. Curr Neurol Neurosci Rep 2017; 17(2): 19.
Shirahata M, Ono T, Stichel D, Schrimpf D, Reuss DE, Sahm F, et al. Novel, improved grading system(s) for IDH-mutant astro-cytic gliomas. Acta Neuropathol 2018; 136(1): 153–66.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360(8): 765–73.
Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, et al. Patients with IDH1 wild type anaplastic astrocyto-mas exhibit worse prognosis than IDH1-mutated glioblasto-mas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classifications of gliomas. Acta Neuropathol 2010; 120(6): 707–18.
Miller JJ, Shih HA, Andronesi OC, Cahill DP. Isocitrate dehy-drogenase-mutant glioma: Evolving clinical and therapeutic implications. Cancer 2017; 123(23): 4535–46.
Khan I, Waqas M, Shamim MS. Prognostic significance of IDH1 mutation in patients with glioblastoma multiforme. J Pak Med Assoc 2017; 67(5): 816–7.
Hainaut P, Hollstein M. P53 and human cancer: the first ten thousand mutations. Adv Cancer Res 2000; 77: 81–137.
Peraud A, Kreth FW, Wiestler OD, Kleihues P, Reulen HJ. Prog-nostic impact of TP53 mutations and P53 protein overexpres-sion in supratentorial WHO grade II astrocytomas and oligo-astrocytomas. Clin Cancer Res 2002; 8(5): 1117–24.
Liu XY, Gerges N, Korshunov A, Sabha N, Khuong-Quang DA, Fontebasso A, et al. Frequent ATRX mutations and loss of ex-pression in adult diffuse astrocytic tumors carying IDH1/IDH2 and TP53 mutations. Acta Neuropathol 2012; 124(5): 615–25.
Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. Altered telomeres in tumors with ATRX and DAXX muta-tions. Science 2011; 333(6041): 425.
Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde R, et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012; 3(7): 709–22.
Wiestler B, Capper D, Holland-Letz T, Korshunov A, von Deimling A, Pfister SM, et al. ATRX loss refines the classification of an-aplastic gliomas and identifies a subgroup of IDH mutant as-trocytic tumours with better prognosis. Acta Neuropathol 2013; 126(3): 443–51.
Sipos T, Kövecsi A, Kocsis L, Nagy-Bota M, Pap Z. Evaluation of Microvascular Density in Glioblastomas in Relation to p53 and Ki67 Immunoexpression. Int J Mol 2024; 25(12): 6810.
Kloosterhof NK, Bralten LB, Dubbink HJ, French PJ, van den Bent MJ. Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma? Lancet Oncol 2011; 12(1): 83–91.
Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Felsberg J, et al. 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 2009; 118(4): 469–74.
Sturm D, Witt H, Hovestadt V, Khouong-Quang DA, Jones DT, Konermann C, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblas-toma. Cancer Cell 2012; 22(4): 425–37.
Capper D, Weissert S, Balss J, Habel A, Meyer J, Jäger D, et al. Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 2010; 20(1): 245–54.
Pekmezci M, Rice T, Molinaro AM, Walsh KM, Decker PA, Han-sen H, et al. Adult infiltrating gli¬omas with WHO 2016 inte-grated diagnosis: additional prog¬nostic roles of ATRX and TERT. Acta Neuropathol 2017; 133(6): 1001–16.
Chen JR, Yao Y, Xu HZ, Qin ZY. Isocitrate dehydrogenase (IDH)1/2 mutations as prognostic markers in patients with glioblastomas. Medicine (Baltimore) 2016; 95(9): e2583.
Paldor I, Drummond KJ, Kaye AH. IDH1 mutation may not be prognostically favorable in glioblastoma when controlled for tumor location: A case control study. J Clin Neurosci 2016; 34: 117−20.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma mul-tiforme. Science 2008; 321(5897): 1807−12.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360(8): 765−73.
Chaurasia A, Park SH, Seo JW, Park CK. Immunohistochemi-cal analysis of ATRX, IDH1 and p53 in glioblastoma and their correlations with patient survival. J Korean Med Sci 2016; 31(8): 1208−14.
Reuss DE, Sahm F, Schrimpf D, Wiestler B, Capper D, Koelsche C, et al. ATRX and IDH1- R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” di¬agnostic approach for adult astro-cytoma, oligodendroglioma and glioblastoma. Acta Neuropa-thol 2015; 129(1): 133−46.
Cai J, Zhang C, Zhang W, Wang G, Yao K, Wang Z, et al. ATRX, IDH1-R132H and Ki-67 immunohistochemistry as a classification scheme for astrocytic tumors. Oncoscience 2016; 3(7−8): 258−65.
Schmidt MC, Antweiler S, Urban N, Mueller W, Kuklik A, Meyer-Putlitz B, et al. Impact of genotype and morphology on the prognosis of glioblastoma. J Neuropathol Exp Neurol 2002; 61(4): 321−8.
Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Pa-tre PL, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004; 64(19): 6892−9.
Erbayraktar Z, Erbayraktar S, Erkan EP. Targeted therapy for glioblastoma: Evaluation of current strategies and new targets. J Nerv Syst Surg 2015; 5(2): 59−68.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer R, et al. Effects of radiothera¬py with concomitant and adjuvant temozolomide versus ra¬diotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10(5): 459−66.
Ekici MA, Bulut T, Tucer B, Başarslan SK, Kurtsoy A. Prognostic factors in patients with glioblastoma multiforme (clinical re-search). Turk J Med Sci 2013; 43(5): 795−804.
Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, et al. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 1998; 57(7): 684−9.
Hegi ME, Diserens AC, Godard S, Dietrich PY, Regli L, Oster-mann S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with te-mozolomide. Clin Cancer Res 2004; 10(6): 1871−4.
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 multi-forme. J Natl Cancer Inst 2001; 93(16): 1246−56.
