scholarly journals P14.23 Risk of venous thromboembolism (VTE) in grade II-IV gliomas as a function of molecular subtype

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii71-iii72
Author(s):  
M Diaz ◽  
J Jo ◽  
D Schiff
Keyword(s):  
Molecular Subtype ◽  
Methylation Status ◽  
Promoter Hypermethylation ◽  
Molecular Testing ◽  
Lower Grade ◽  
Idh Mutation ◽  
Mgmt Methylation ◽  
Who Grade ◽  
Grade Ii ◽  
Grade Iii

Abstract BACKGROUND VTE affects up to 30% of patients with glioblastoma (GBM, WHO grade IV), but little is known about its incidence in lower-grade gliomas (LGG, WHO grade II-III). It has been suggested that isocitrate dehydrogenase (IDH) mutation status dramatically decreases the incidence of VTE in glioma patients, through a combination of F3 promoter hypermethylation leading to lower expression of the procoagulant protein tissue factor, and an increased production of D-2-hydroxyglutarate, which has anticoagulant properties (Unruh et al, 2016). Our objective was to determine the incidence of VTE in LGG and stratify VTE risk by molecular subtype in gliomas grade II-IV. MATERIAL AND METHODS We performed a retrospective analysis of 590 glioma patients with molecular testing seen at our institution (UVa) from January 2005 to August 2017. We divided LGG patients into 3 groups: IDH-wildtype (IDHwt); IDH-mutant (IDHmt), 1p/19q-codeleted; and IDHmt, 1p/19q-intact. GBM patients were divided according to MGMT methylation status. Estimates of cumulative incidence of VTE were calculated with death as competing risk, and significance testing was determined using the Fine and Gray model. RESULTS Of 256 LGG patients (147 grade II and 109 grade III), 81 were IDHwt, 113 IDHmt and 1p/19q-codeleted, and 62 IDHmt and 1p/19q-intact. There were 334 GBM patients, with MGMT methylation status available in 263 (98 (37%) methylated and 165 (63%) unmethylated). With a median follow-up of 545 days, the overall incidence of VTE was 8.2% for grade II, 9.2% for grade III and 30.5% for grade IV. The 6-, 12- and 24-month VTE incidence was 4.1%, 4.8% and 5.4% respectively for grade II, 4.6%, 7.3% and 9.2% for grade III and 23.1%, 26.6% and 29% for grade IV. In LGG patients, VTE incidence was slightly higher in IDHwt tumors (11.1%) vs IDHmt, 1p/19q-codeleted (8.8%) and IDHmt, 1p/19q-intact tumors (4.8%). However, this difference was not statistically significant (IDHwt vs IDHmt, 1p/19q-codeleted, sub-distribution hazard ratio (SHR)=1.67, 95% CI=0.59–4.72; IDHwt vs IDHmt, 1p/19q-intact, SHR=1.87, 95% CI=0.54–6.53). In GBM patients, there was no difference in the VTE incidence according to MGMT methylation status (SHR=0.99, 95% CI=0.64–1.54). CONCLUSION In our cohort, the risk of VTE in GBM patients was consistent with historical data; patients with LGG also had a higher VTE risk compared to the general population. In contrast to other retrospective studies in which the incidence of VTE for grade II-IV IDHmt gliomas was 0% (Unruh et al, 2016; Nazari et al, 2018), our data suggest that VTEs do occur in IDHmt LGG patients, although at a lower rate than in IDHwt. MGMT methylation does not seem to influence the incidence of VTE. VTE risk stratification in GBM patients based on IDH mutation is forthcoming.

scholarly journals Risk of Venous Thromboembolism in Grade II-IV Gliomas as a Function of Molecular Subtype

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011414
Author(s):  
Maria Diaz ◽  
Jasmin Jo ◽  
Mark Smolkin ◽  
Sarah Jane Ratcliffe ◽  
David Schiff
Keyword(s):  
Venous Thromboembolism ◽  
Promoter Methylation ◽  
Cumulative Incidence ◽  
Molecular Subtype ◽  
Methylation Status ◽  
World Health ◽  
Molecular Testing ◽  
Lower Grade ◽  
Idh Mutation ◽  
Grade Ii

Objective:To determine the incidence of venous thromboembolism (VTE) in lower-grade gliomas (LGG, World Health Organization (WHO) grades II-III) and to stratify the risk of VTE by molecular subtype in gliomas grade II-IV, we performed a retrospective review of a large cohort of glioma patients.Methods:We performed a retrospective analysis of a cohort of 635 adult glioma patients with molecular testing seen at the University of Virginia with a diagnosis of glioma established from January 2005 to August 2017. Estimates of cumulative incidence of VTE were calculated with death as competing risk; significance was determined using the Fine and Gray model.Results:Of 256 LGG patients, 81 were isocitrate dehydrogenase (IDH) wild-type; 113 IDH mutant, 1p/19q codeleted; and 62 IDH mutant, 1p/19q intact. With a median follow-up of 17.9 months, the overall cumulative incidence of VTE was 8.2% for grade II (147 patients), 9.2% for grade III (109 patients), and 30.5% for grade IV (334 patients). In grade II-IV patients, absence of an IDH mutation was associated with a three-fold increase in VTE risk when compared to IDH-mutant patients (HR=3.06, 95% CI=2.03-4.64). In GBM patients, there was no difference in VTE incidence according to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.Conclusion:Patients with LGG have a higher VTE risk compared to the general population, which is decreased, but not eliminated, in the presence of an IDH mutation. MGMT promoter methylation in GBM does not affect the incidence of VTE.

scholarly journals The Expression of Progesterone Receptors in Meningiomas of Different Grades

2019 ◽  
Vol 8 (2) ◽  
pp. 65-69
Author(s):  
Mohammad Tahir ◽  
Tehreem Atif ◽  
Summaya Sohail ◽  
Arfa Nawazish ◽  
Huma Mushtaq
Keyword(s):  
Progesterone Receptor ◽  
Treatment Options ◽  
Progesterone Receptors ◽  
Lower Grade ◽  
Immunoperoxidase Method ◽  
Nuclear Staining ◽  
Who Grade ◽  
Grade Ii ◽  
Who Grade Iii ◽  
Grade Iii

Background: Meningiomas are slow growing intracranial and intraspinal neoplasms with a tendency to recur locally. WHO grades them as I (benign), II (atypical) and III (anaplastic) in order of their increasing aggressiveness, based on histological parameters and brain parenchymal invasion. Progesterone receptors (PR) are more prevalent amongst the lower grade meningiomas. The objective of this study was to determine the immunohistochemical expression of progesterone receptors in meningiomas of different grades.Material and Methods: A total of 100 cases were selected over a period of 2.5 years. Three to five microns’ thick sections stained with Hematoxylin and Eosin were examined microscopically by a team of two Histopathologists and graded into grades I, II and III, according to 2016 WHO classification criteria. Another section of the original tumor was stained with progesterone receptor antibody using the conventional immunoperoxidase method. Stained slides were than examined by the same team of Histopathologists and declared positive (if nuclear staining was observed in more than 10% of tumor cells) or negative. Statistical analysis was done using SPSS version 21.Results: Out of a total of 100 cases of meningioma, there were 79 cases of benign/typical WHO grade I, 15 cases of atypical/ WHO grade II and 6 cases of anaplastic/ WHO grade III tumor. PR status was positive in 89.8 % (71/79) of grade I meningiomas and 46.6 % (7/15) of grade II/Atypical meningiomas. The 06 cases of Anaplastic/WHO grade III tumors were negative for PR. There was a higher prevalence of Progesterone receptors in female patients (89.8%; 53/59) as compared to male meningioma patients (60.9%; 25/41).Conclusion: We observed a decreased expression of progesterone receptor in higher grades of meningioma in this study. It is an effort to explore conservative treatment options for inoperable lesions, as anti-progesterone therapy may hold a promise as a new treatment option in the near future.

scholarly journals IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas

2018 ◽  
Vol 20 (11) ◽  
pp. 1505-1516 ◽  
Author(s):  
Lei Zhang ◽  
Liqun He ◽  
Roberta Lugano ◽  
Kenney Roodakker ◽  
Michael Bergqvist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Lower Grade ◽  
Idh Mutation ◽  
Wild Type ◽  
Who Grade ◽  
Mutation Status ◽  
Grade Ii ◽  
Grade Ii Glioma

Abstract Background Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype. Methods Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro. Results Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro. Conclusion IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.

scholarly journals The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors

Neurosurgery ◽  
2015 ◽  
Vol 78 (3) ◽  
pp. 401-411 ◽  
Author(s):  
Mohammed Jaber ◽  
Johannes Wölfer ◽  
Christian Ewelt ◽  
Markus Holling ◽  
Martin Hasselblatt ◽  
...  
Keyword(s):  
Aminolevulinic Acid ◽  
Methylation Status ◽  
Imaging Features ◽  
High Grade ◽  
Ki 67 ◽  
Who Grade ◽  
Fet Pet ◽  
Grade Ii ◽  
Grade Iii ◽  
Mib 1

Abstract BACKGROUND: Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade. OBJECTIVE: The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [18F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics. METHODS: Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and 18F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors. RESULTS: Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and 18F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P < .001) and Ki-67/MIB-1 index (P < .001), but not with MGMT promoter methylation status, IDH1 mutation status, or 1p19q co-deletion status. The Ki-67/MIB-1 index in fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted. CONCLUSION: Age, tumor volume, and 18F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased Ki-67/MIB-1 index and high-grade pathology. Whether fluorescence in grade II gliomas identifies a subtype with worse prognosis remains to be determined.

Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis

2010 ◽  
Vol 120 (6) ◽  
pp. 719-729 ◽  
Author(s):  
Philippe Metellus ◽  
Bema Coulibaly ◽  
Carole Colin ◽  
Andre Maues de Paula ◽  
Alexandre Vasiljevic ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Idh Mutation ◽  
Who Grade ◽  
Dismal Prognosis ◽  
Grade Ii ◽  
Who Grade Ii Gliomas

scholarly journals IDH-wildtype lower grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification

2020 ◽  
Author(s):  
Giulia Berzero ◽  
Anna Luisa Di Stefano ◽  
Susanna Ronchi ◽  
Franck Bielle ◽  
Chiara Villa ◽  
...  
Keyword(s):  
Histological Grade ◽  
Lower Grade ◽  
Who Grade ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Prognostic Stratification ◽  
Grade Ii ◽  
Definition Of ◽  
Promoter Mutations ◽  
Grade Iii

Abstract Background IDH-wildtype (IDHwt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. Methods We searched retrospectively all patients diagnosed with diffuse WHO grade II and III gliomas at our center (1989-2020). Results Out of 517 grade II gliomas, 47 were “diffuse astrocytomas, IDHwt”. Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found TERT promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%) but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs. 19 months for IDHwt grade III gliomas (p< 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update3. Median OS in this subset was 42 months, which was shorter compared to patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 months), but substantially longer compared to IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 months, p<0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 months). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Conclusions Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

CBIO-18. TP53-MUTANT OLIGODENDROGLIOMA: A SINGLE INSTITUTION CASE SERIES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi30-vi31
Author(s):  
Mason Webb ◽  
Sani Kizilbash ◽  
Thomas Kollmeyer ◽  
Robert Jenkins ◽  
Sarah Sung ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Tp53 Mutation ◽  
Case Series ◽  
Molecular Testing ◽  
Diffuse Glioma ◽  
Who Grade ◽  
Tp53 Mutations ◽  
Grade Ii ◽  
Who Grade Iii ◽  
Grade Iii

Abstract TP53 mutations are frequent in IDH-mutant astrocytomas but unusual in oligodendroglioma and the clinical significance of TP53 mutations in oligodendroglioma are not well characterized. We reviewed genetically defined oligodendroglioma (i.e., IDH-mutant, whole-arm 1p/19q-codeleted diffuse glioma) cases that were molecularly profiled (2017-2020) at our institution and identified 7 cases with TP53 mutation (9%; n=76). Molecular testing was performed using targeted neuro-oncology NGS panel (50-gene mutation and/or 187-gene mutation/rearrangement) and OncoScan™ microarray. Four (of 7) patients were female. Median age at diagnosis was 43 years (range, 23-63). Most common presenting symptom was seizures (3 of 7). All tumors were supratentorial. Histologically, 3 tumors were WHO grade II and 4 were WHO grade III. Two (of 3) patients with a WHO grade II tumor underwent biopsy and radiotherapy at diagnosis followed by temozolomide at recurrence (progression at 67 and 157 months after diagnosis; overall survival of 124 and 201 months). Three (of 4) patients with a WHO grade III tumor were diagnosed within the last two years and are currently progression-free after standard therapy. Molecularly, in addition to TP53 mutation(s), all cases had an IDH1 and TERT promoter mutation as well as other gene mutation(s) including FUBP1 (n=5), SETD2 (n=4), PIK3R1 (n=4), PIK3CA (n=3), NF1 (n=3) and CIC (n=3). In 3 (of 7) cases, the mutational profile with high mutation count enriched for C >T/G >A transitions was highly suggestive of a hypermutation phenotype (2 cases were recurrent tumors treated with temozolomide; a recurrent and a treatment-naïve tumor had mismatch repair gene mutation). Five (of 7) cases, including the 3 hypermutant cases, lacked functional TP53 (1 case with 2 mutations, 2 cases with 1 mutation plus loss of other copy, 2 cases with 1 mutation plus copy neutral loss-of-heterozygosity). TP53 mutations are uncommon in oligodendroglioma and appear enriched in hypermutant tumors.

Gene expression signature to predict radiation response in lower-grade gliomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2019-2019
Author(s):  
David C Qian ◽  
Joseph A. Marascio ◽  
Stewart G. Neill ◽  
Kimberly B. Hoang ◽  
Jeffrey J. Olson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lower Grade ◽  
Training Set ◽  
Who Grade ◽  
Internal Validation ◽  
Expression Levels ◽  
Expression Signature ◽  
Grade Ii ◽  
Validation Set ◽  
Grade Iii

2019 Background: Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases. Methods: Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II–III gliomas) treated by surgery and adjuvant RT were randomized 1:1 to a training set or an internal validation set. Using patients in the training set, association between gene expression from resected tumor and progression-free survival (PFS) as well as overall survival (OS) was evaluated with adjustment for clinicopathologic covariates. A genomic risk score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was subsequently validated in the internal validation set of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA). Results: From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1, involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition. High GRS, defined as having a GRS in the top third, was significantly associated with worse outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the training set (OS HR 2.74, P < 0.001; PFS HR 1.61, P = 0.014). These findings were further validated in the internal validation set (OS HR 1.84, P = 0.015; PFS HR 1.58, P = 0.027) and again in the CGGA external validation set (OS HR 1.72, P = 0.001). Association between GRS and outcomes was observed only among patients who received RT (RT alone or CRT), in both TCGA and CGGA. Conclusions: This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with survival only among patients whose treatments included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes to determine high/low GRS may be considered in the multidisciplinary management of LGGs.

scholarly journals MPC-13 The evaluation of the shift of trend in lower grade glioma diagnoses based on each era`s criteria

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi17-vi18
Author(s):  
Eriel Sandika Pareira ◽  
Makoto Shibuya ◽  
Kentaro Ohara ◽  
Yu Nakagawa ◽  
Tokunori Kanazawa ◽  
...  
Keyword(s):  
Molecular Characteristics ◽  
Lower Grade ◽  
Comparative Genome Hybridization ◽  
Diffuse Glioma ◽  
Idh Mutation ◽  
Morphological Criteria ◽  
Lower Grade Glioma ◽  
Sanger Sequence ◽  
Grade Ii ◽  
Grade Iii

Abstract It is found that molecular characteristics in lower grade gliomas (LrGGs) such as codeletion of 1p/19q and IDH mutation was found to be more accurate to predict the patient`s clinical outcome compared to morphological diagnoses alone. Since the revision WHO2016 classification of LrGGs, molecular characteristics were implemented as diagnostic standard for LrGGs diagnoses. In the other hand, morphological diagnostic standard before WHO2016 classification era was determined by different considerations and therapeutic strategies. The malignancy grades were also majorly determined by morphological diagnoses only. This study re-evaluated 20 years of LrGG cases in single institution based on WHO2007 morphological criteria and compared them to the original institutional diagnoses from each era. The study samples were originally grade II-III diffuse glioma-diagnosed cases resected from 1990 to 2016. Biopsy cases were excluded. IDH mutation was analyzed by Sanger sequence and 1p/19 codeletion status was analyzed by Comparative Genome Hybridization (CGH). As the result 93 cases were collected and based on original diagnoses, more than 50% cases are astrocytomas. Compared to re-assessment by morphological diagnoses (WHO 2007), case numbers of astrocytoma diagnoses are decreased whereas oligodendroglioma and oligoastrocytoma case numbers are increased. But, based on WHO2016 criteria, the case number of astrocytomas is again found to be increased. From comparison between original institutional diagnoses and re-assessment results, it is found that there is a shift of trend from astrocytoma to oligodendroglioma and from grade II to grade III. Comparison between morphological diagnoses (WHO2007) and molecular (WHO2016) found that astrocytoma diagnoses remain unchanged meanwhile 45% of oligodendroglioma diagnoses were shifted into astrocytomas. There is a probability that there are high frequency of morphologically diagnosed oligodendroglioma tumors which are having molecular characteristics of astrocytoma. There is a trend that diagnosed grade II LrGGs are actually grade III based on re-assessment diagnosis.

Malignant transformation-related genes in meningiomas: allelic loss on 1p36 and methylation status of p73 and RASSF1A

2007 ◽  
Vol 107 (2) ◽  
pp. 398-404 ◽  
Author(s):  
Yukimi Nakane ◽  
Atsushi Natsume ◽  
Toshihiko Wakabayashi ◽  
Sachie Oi ◽  
Motokazu Ito ◽  
...  
Keyword(s):  
Malignant Transformation ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Genetic Alterations ◽  
Allelic Loss ◽  
Lower Grade ◽  
Who Grade ◽  
Genetic Fingerprint ◽  
I 11 ◽  
Grade Ii

Object Analysis of meningiomas supports the suggestion that loss of heterozygosity (LOH) of chromosome arm 1p plays an important role in malignancy. The aim of this study was to identify genes related to meningioma progression from the benign state to the atypical and anaplastic states by examining 1p LOH and the promoter methylation of RASSF1A and p73. Methods The authors studied 40 surgical specimens (22 WHO Grade I, 11 Grade II, and seven Grade III) obtained in 37 patients with meningioma. The LOH at 1p36 was analyzed using microsatellite markers, and promoter methylation of p73 and RASSF1A was analyzed using methylation-specific polymerase chain reaction. Results No 1p LOH was detected in the Grade I tumors, whereas it was detected in more than 80% of the Grade II and III tumors. Methylation of the p73 promoter was observed in 81.8 and 71.4% of the Grade II and III tumors, respectively, but it was not observed in any of the Grade I tumors; methylation of the RASSF1A promoter was observed in 18.2, 63.6, and 42.9% of the Grade I, II, and III tumors, respectively. Interestingly, 1p LOH and p73 promoter hyper-methylation were detected in the malignantly transformed tumors but not in the lower-grade primary ones. Conclusions Based on the hypothesis that meningiomas cumulatively acquire genetic alterations and thus progress from the benign to the atypical and anaplastic states, genetic alterations in the methylation status of p73 or RASSF1A along with 1p LOH may result in the malignant transformation of a meningioma. This type of genetic fingerprint may play both diagnostic and therapeutic roles.

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