Role of cyclin D1 in glial tumors—A retrospective and observational study

Aim: High-grade glial tumors remain as one of the most lethal malignancies. Cyclin D1 is expressed in some human malignancies and is the potential target of intervention. The present study aims to determine the relationship of cyclin D1 expression with other clinicopathological parameters. Materials and Methods: A cross-sectional study was carried out in a tertiary care center. Biopsy proven 66 cases of glial tumor patients were included in the study. The patients with incomplete clinical details were excluded from the study. Immunohistochemistry using antibodies for IDH 1 and cyclin d1 was done in all the cases. Glial tumors were reclassified according to WHO 2016 classification. Data analysis was performed using SPSS 26.0 for the windows. Result: Among 66 patients, 49 (74.3%) were males and 17 (25.7%) were females. The age of the patients ranged from 20 years to 70 years. Overall, 6.02% were of grade I Glial tumors, 22.7% were of grade II Glial tumors, 19.6% patients were of grade III Glial tumors, and 51.6% patients were of grade IV Glial tumors. Of 66 samples tested cyclin D1 was positive in 25 (37.87%) as high expressers and 7 (10.60%) were low expressers. Our study showed a significant correlation between the expression of cyclin D1 with grade and IDH mutation status, No significant correlation of cyclin D1 was noted with age or sex of the patient. Conclusion: Cyclin D1 was associated with a higher grade of the glial tumor. It can be a potential marker both for prognosis and treatment of glial tumors.

The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Correlation Between Apparent Diffusion Coefficient and IDH-1/1p19q Genotype of Glioma / 肿瘤防治研究

Objective To investigate the correlation between ADC value and glioma IDH-1/1p19q genotype. Methods The MRI features and molecular pathological results of 69 patients with pathologically confirmed diagnosis of WHO grade Ⅱ/Ⅲ glioma between March 2013 and December 2020 were retrospectively analyzed. The diagnostic performance of ADC values on glioma genotypes (IDH-1, 1p19q) was evaluated using the ROC curve of the subjects' working characteristics. Results The ADCmean, ADCmin, rADCmean, and rADCmin in the IDH-1 mutation group were significantly higher than those in the IDH-1 wild group (P < 0.05, P < 0.01, P < 0.05, P < 0.01). The use of the rADCmin threshold (0.979×103mm2/s) had the highest efficacy (AUC=0.770) for diagnosis of IDH-1 mutant and IDH-1 wild-type gliomas as well as sensitivity and specificity of 84.61% and 59.09%, respectively. Conclusion ADC can be used as an imaging biomarker for noninvasive prediction of IDH-1 mutant and wild-type Ⅱ /Ⅲ gliomas.

Berberine targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia with IDH1 mutation / 中国天然药物

Metabolic reprogramming, a newly recognized trait of tumor biology, is an intensively studied prospect for oncology medicines. For numerous tumors and cancer cell subpopulations, oxidative phosphorylation (OXPHOS) is essential for their biosynthetic and bioenergetic functions. Cancer cells with mutations in isocitrate dehydrogenase 1 (IDH1) exhibit differentiation arrest, epigenetic and transcriptional reprogramming, and sensitivity to mitochondrial OXPHOS inhibitors. In this study, we report that berberine, which is widely used in China to treat intestinal infections, acted solely at the mitochondrial electron transport chain (ETC) complex I, and that its association with IDH1 mutant inhibitor (IDH1mi) AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro andin vivo. Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia (AML) patients using combinatory mitochondrial targeted medicines, particularly those who are resistant to or relapsing from IDH1mi.

Progress of targeted therapy for acute myeloid leukemia / 白血病·淋巴瘤

The treatment of acute myeloid leukemia (AML) has made a great progress in recent years owing to the emergence of targeted drugs. While the problems such as drug resistance, the increasing incidence of adverse reactions of the combined therapies, the lack of the effective therapy targets became growing concerns with the further development of studies, which has posed a big challenge to the therapy strategies of AML. This article introduces the progress of the latest clinical trial outcomes in targeted therapy for AML at the 63rd American Society of Hematology (ASH) annual meeting which reported some hot issues like options for the treatment timing of targeted therapy, the selection for the drugs and the combined drugs.

Prognostic value of mutations in isocitrate dehydrogenase 1 (IDH1) and reverse telomerase transcriptase (TERT ) in Argentine patients` gliomas / Valor pronóstico de mutaciones en Isocitrato dehidrogenasa1 (IDH1) y Telomerasa transcriptasa reversa (TERT ) en gliomas de pacientes argentinos

Background and aim: Gliomas are the most common primary brain tumors, classified according to their histopathological and genetic features. Tumorigenesis depends on alterations in different genes. The aim of this study was the identification of mutations in IDH1 and TERT genes in gliomas of Argentine patients and to correlate them with clinical features and prognosis. Methods: DNA was isolated from 19 biopsies with different glioma grades matched with blood samples. IDH1 and TERT mutations were studied by PCR amplifica-tion and sequencing. Results: Six out of seven patients with low-grade glioma (grade II) harbor IDH1 mutations, mainly without tumor growth and overall survival of more than 12 months. Eleven out of twelve patients with high-grade gliomas (grade III/IV) showed wild type IDH1, mainly with tumor growth and shorter survival than low-grade gliomas. Mutated TERT promoter was present in 5 out of 11 high-grade gliomas, showing the prevalence of polymorphic C allele. In 1 out of 5 low-grade gliomas with a predominance of T allele. TERT and IDH1 mutations were mutually exclusive in most gliomas. Conclusions: Our results show that genetic tests provided a more accurate prognosis than histopathological analysis. The evolution of gliomas can be predicted primarily by the mutational status of IDH1 and secondarily by other markers, such as TERT mutational status

Antecedentes y objetivo: los gliomas son los tumores cerebrales primarios más comunes y se clasifican según sus características histopatológicas y genéticas. La tumorigénesis depende de alteraciones en diferentes genes. El objetivo de este estudio fue identificar mutaciones en los genes IDH1 y TERT en gliomas de pacientes argentinos y correlacionarlos con la evolución clínica. Métodos: se obtu-vieron 19 muestras pareadas de ADN de gliomas y de la sangre. Las mutaciones en IDH1 y TERT se analizaron por PCR y secuenciación. Resultados: la IDH1 mutada se encontró en 6 de los 7 gliomas de bajo grado (grado II), mayormente sin crecimiento tumoral y una sobrevida mayor de 12 meses. La IDH1 salvaje estaba presente en 11 de los 12 gliomas de alto grado (grado III y IV) mayormente con crecimiento tumoral y menor sobrevida que los tumores de bajo grado. Las mutaciones en el promotor del gen TERT se observaron en 5 de los 11 gliomas de alto grado, con la prevalencia de alelo polimórfico C, en cambio, en gliomas de bajo grado TERT mutado estaba presente en 1 de los 5 gliomas con predominio del alelo T. Las mutaciones en IDH1 y TERT fueron mutuamente excluyentes en la mayoría de los gliomas. Conclusiones: el análisis genético provee un pronóstico más certero que el análisis histopatológico. Nuestros resulta-dos muestran que la evolución de gliomas puede predecirse primariamente por el estado mutacional de IDH1 y secundariamente por mutaciones en otros marcadores tales como el TERT

A Dual Genetic Alteration (Mitochondrial and Nuclear DNA): First Case in Malaysia Detected in Glioblastoma Multiforme

@#Although the precise etiology of Glioblastoma multiforme (GBM, WHO grade IV) remains unknown, its progression is believed to be driven by the accumulation of multiple genetic alterations. Here, we report a case of a patient who developed GBM, and associated with dual alterations, particularly 4977-bp deletion in mtDNA (mtDNA4977) and p.Arg132His (R132H) mutation in IDH1. A 35-year old Malaysian woman patient who primary diagnosed with astrocytoma WHO grade I and subsequently after four years developed a GBM, was detected with a mtDNA4977. This deletion appears to be a sporadic mutation. Additionally, analysis of patient’s tumor tissue also found to harbor a heterozygous IDH1 R132H mutation. This represents the first case report of coexisting mtDNA4977 together with IDH1 R132H mutation in a Malaysian patient of GBM. The findings of dual alterations could be of therapeutic benefit if these alterations were justified to be contributing to GBM growth and aggressiveness.

Effect of systemic inflammation response index on clinical prognosis of patients with glioma and its relationship with IDH1 mutation / 实用肿瘤学杂志

Objective The objective of this study was to investigate the effect of systemic inflammation response index(SI-RI)on clinical prognosis of patients with glioma and its relationship with dehydrogenase 1(IDH1)mutation.Methods Eighty patients with glioma who underwent surgery in the department of Neurosurgery were collected from August 2006 to November 2015.The best clinical cutoff value for SIRI was determined using operating characteristic curve(ROC)and grouped accordingly.The Kaplan-Meier and log-rank methods were used to analyze the postoperative survival of the two groups of patients.The independent clinical prognos-tic factors were evaluated by Cox′s proportional hazards regression model.The IDH1 mutation was detected by immunohistochemistry and DNA sequencing.Results SIRI was an independent prognostic factor of glioma,and the best clinical cutoff value was 0.67 × 109/L.The median progress free survival(PFS)and overall survival(OS)of patients with low SIRI group were 46.90 months and 57.90 months,and the median PFS and OS of patients with high SIRI group were 31.78 months and 47.22 months,respectively.There was significant difference between the two groups in the median survival time of PFS and OS by log-rank method(P<0.05).Univa-riate and multivariate analysis showed that age,gender,type of surgery,WHO stage,SIRI and IDH1 mutation were the independent prognostic factors in neurostein stromal tumors.Patients with low-grade SIRI and glioma with IDH1 mutation have a better prognosis than other conditions.Conclusion SIRI is an independent prognostic factor of glioma.It is simple,convenient and reproducible,and may be used to predict the prognosis of patients with glioma.

Correlations of mutations of IDH1,IDH2,p53 gene and Ki-67 protein expression in gliomas with the clini cal features of pathological grading / 实用医学杂志

Objective To investigate the mutations of IDH1,IDH2,p53 gene,and Ki-67 protein expression in different grade of gliomas and identify the association with its clinical relevance. Methods The mutations of IDH1,IDH2 and p53 gene were detected by direct DNA sequencing,and protein expression of Ki-67 was analyzed by immunohistochemistry. The correlations between gender,age,tumor site,differentiation degree and pathological type of patients were analyzed. Results R132H mutation of IDH1 gene was detected in 32.6% samples (14/46 cases),of which the proportion of WHO classification grade Ⅱ was 40.0%,and grade Ⅲ was 58.3%. IDH1 mutations were shown correlated with age,pathology level Ⅱ-Ⅲ,and Ki-67 low expression. p53 mutations were detected in 4 glioblastomas,with mutations located at exon 7,8. IDH1 gene mutation was negatively correlated with Ki-67 expression. Conclusions The proportion of IDH1 gene mutation in different pathological types of gliomas is different,which is the highest in gradeⅡ~Ⅲ. It is suggested that the subtypes should be listed independently by routine tests. Mutations in p53 gene are more common in primary glioblastomas and may be associated with adverse outcomes. The combined detection of DH1,p53 and Ki-67 is conducive to the diagnosis and prognosis of glioma.

The clinicopathological significances of LDHA and mutant p53 co-expression in gliomas / 实用医学杂志

Objective To investigate the clinicopathological significances of LDHA/mutant p53 co-expres-sion in gliomas. Methods According to the 2016 WHO CNS,archived 68 gliomas were collected and analyzed retrospectively. The co-expression of LDHA/mutant p53 was detected by immunohistochemical staining. Results High expression of LDHA alone was always found in high grade gliomas(48.5%). Mutant p53 high expression was usually observed in glioblastomas (26.5%). There was a close relationship between co-expression of LDHA/mutant p53 in glioblastoma(27.9%,P = 0.005),or gliomas with high histological grading(27.9%,P = 0.002). Conclusions Co-expression of LDHA/mutant p53 in tumor cells might be a specific immunohistochemical pheno-type of gliomas,and may help for distinguishing glioblastoma and other high grade gliomas from low grade gliomas.

The correlation between microvessel density, IDH1 mutation and the malignancy of glioma and its clinical significance / 肿瘤研究与临床

Objective To study the correlation between microvessel density (MVD),isocitrate dehydrogenase 1 (IDH1) mutation and the malignancy of glioma,and its clinic significance.Methods The data and specimens of 40 patients with gliomas confirmed by surgery and pathology were collected.The relation between IDH1 mutation (detected by genetic sequence),MVD (detected by immunohistochemical coloration) and the malignancy of glioma was explored.5 cases of normal human brain tissues were used for comparative study.Results In normal brain tissue,Ⅰ,Ⅱ,Ⅲ,Ⅳ glioma,MVD counts were 8.12±1.64,25.10±1.27,27.00±1.98,42.80±10.75 and 56.50±5.23,respectively,and the overall difference was statistically significant (H =35.42,P ＜ 0.05).The MVD counts in low-grade glioma (Ⅰ-Ⅱ) and high-grade glioma (Ⅲ-Ⅳ) were 23.94±8.03 and 45.54±8.19,respectively,and the difference was statistically significant (t =-8.369,P ＜ 0.001).No mutation was found in normal human brain tissue,while in 20 cases of glioma specimens,there was IDH1 mutation with R132 as the mutation site and a MVD count of 31.11±13.47,and the other 20 cases of glioma specimens experienced no IDH1 mutation and the corresponding MVD count was 40.54±12.11.The difference of MVD counts of low-grade glioma and high-grade glioma was statistically significant (t =2.328,P=0.025).Conclusion MVD can be used as one of the histopathological grading metrics for glioma.IDH1 mutation occurs more frequently in grade Ⅱ and Ⅲ gliomas with R132 as the mutation site.

Correlation of Genomic Characteristic with Disease Progression in Polycythemia Vera / 天津医药

Objective To screen mutations in genes including ASXL1, TET2, IDH1, IDH2, SETBP1, MPL515, JAK2 exon 12 and JAK2V617 in 135 polycythemia vera (PV) patients. To assess progreasson and genomics characteristics post polycythemic myelofibrosis. Methods DNA sequencing of ASXL1(Exon12),TET2 (Exons 3-11),IDH1(Exon4),IDH2(Ex-on4),SEPBP1(Exon4),JAK2 exon 12 and MPL515 (Exon 10) genes were carried out using Sanger method. JAK2V617 muta-tion was detected by allele-specific PCR in patients with PV. In the mean time, the mutation load of JAK2V617F allele (V617F%) was evaluated by real-time PCR using Tagman MGB probe. Then, the significant of gene mutations and clinical outcomes of post-PV Myelofibrosis(PPMF)was analyzed. To study risk factors of PPMF, logistic regression were employed. Results ASXL1, TET2, IDH1, IDH2 were mutated in 7.69%(8/104), 5.26%(1/19) , 0.08%(1/120) and 0.08%(1/121) of all PV patient respectively. JAK2 was mutated in 82.22%(111/135) of PV patients with mutation rate of exon12 of 2.96%(4/135) and there were no mutation of MPL515 and SETBP1 in PV patients. ASXL1 mutation was found in 31.82%(7/22) PPMF patients. Spearman analysis showed that ASXL1 is correlated with JAK2V617F (V617F%) (rs=0.298,P=0.002). The hemo-globin was lower in patients with ASXL1 mutation than patient without mutation (wild type). Leukocyte count, V617F%>50%rate, thrombosis and PPMF were higher in patients with ASXL1 mutation than that of ASXL1 wild type(P＜0.05). ASXL1 mu-tation, V617F%>50% rate and splenomegaly were all risk factors of PPMF. Conclusion ASXL1 mutation is the risk-fac-tor of PPMF and may promote V617F%by some mechanism.

Progress in the study of clinical characteristics and pathogenesis of IDH1/2 gene mutations in acute myeloid leukemia patients / 白血病·淋巴瘤

Acute myeloid leukemia is a group of malignant tumor characterized by chromosome abnormality and/or gene mutations.Its pathogenesis is very complex.Gene mutations in IDH1/2 which encode metabolic enzyme were found by sequencing recently.This discovery aroused interest in the domestic and foreign research group.A series of clinical and basic research was also conducted.This review is based on these studies.

Immunohistochemical Classification of Primary and Secondary Glioblastomas

BACKGROUND: Glioblastomas may develop de novo (primary glioblastomas, P-GBLs) or through progression from lower-grade astrocytomas (secondary glioblastomas, S-GBLs). The aim of this study was to compare the immunohistochemical classification of glioblastomas with clinically determined P-GBLs and S-GBLs to identify the best combination of antibodies for immunohistochemical classification. METHODS: We evaluated the immunohistochemical expression of epidermal growth factor receptor (EGFR), p53, and isocitrate dehydrogenase 1 (IDH-1) in 150 glioblastoma cases. RESULTS: According to clinical history, the glioblastomas analyzed in this study consisted of 146 P-GBLs and 4 S-GBLs. Immunohistochemical expression of EGFR, p53, and IDH-1 was observed in 62.6%, 49.3%, and 11.1%, respectively. Immunohistochemical profiles of EGFR(+)/p53(-), IDH-1(-)/EGFR(+)/p53(-), and EGFR(-)/p53(+) were noted in 41.3%, 40.2%, and 28.7%, respectively. Expression of IDH-1 and EGFR(-)/p53(+) was positively correlated with young age. The typical immunohistochemical features of S-GBLs comprised IDH-1(+)/EGFR(-)/p53(+), and were noted in 3.6% of clinically P-GBLs. The combination of IDH-1(-) or EGFR(+) was the best set of immunohistochemical stains for identifying P-GBLs, whereas the combination of IDH-1(+) and EGFR(-) was best for identifying S-GBLs. CONCLUSIONS: We recommend a combination of IDH-1 and EGFR for immunohistochemical classification of glioblastomas. We expect our results to be useful for determining treatment strategies for glioblastoma patients.

Application of high resolution melting analysis in detecting IDH1 mutation in glioma patients / 中国基层医药

Objective To evaluate the feasibility of detecting the mutation of IDH1 in glioma patients by high resolution melting(HRM) curve analysis.Methods The gene mutation of IDH1 was detected by HRM method in 9 surgical resection paraffin specimens of glioma,and the result was verified by gene sequencing.Results 6 cases of R132H(CGT ＞ CAT) mutation and 1 case of R132C(CGT ＞ TGT) mutation were found by HRM method.The resluts of direct gene sequencing were consistent with HRM method.Conclusion The HRM method in detecting IDH1 mutation is more efficient and convenient than direct sequencing.Moreover,it has advantages of low-cost and suitable for clinical test.