Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas

Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations.

Download Full-text

Pharmacoresistant seizures and IDH mutation in low grade gliomas

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab146 ◽

2021 ◽

Author(s):

Carlos Eduardo Correia ◽

Yoshie Umemura ◽

Jessica R Flynn ◽

Anne S Reiner ◽

Edward K Avila

Keyword(s):

Tumor Resection ◽

Incidence Rates ◽

P Value ◽

Low Grade ◽

Idh Mutation ◽

Wild Type ◽

Mutation Status ◽

Low Grade Gliomas ◽

Idh1 R132h ◽

Idh Mutations

Abstract Purpose Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs. Methods Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥ 2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥ 2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology. Results Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only six were IDH2 R172K. 120 patients (89%) had tumor resection and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray’s P-value= 0.26). Conclusions 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors.The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.

Download Full-text

NEAT1 Is a Novel Oncogenic LncRNA and Correlated with miR-143 in Pediatric Oligodendrogliomas

Pediatric Neurosurgery ◽

10.1159/000514330 ◽

2021 ◽

Vol 56 (2) ◽

pp. 133-139

Author(s):

Secil Ak Aksoy ◽

Melis Mutlu ◽

Rabia Nur Balcin ◽

Mevlut Ozgur Taskapilioglu ◽

Cagla Tekin ◽

...

Keyword(s):

Noncoding Rna ◽

Expression Profiles ◽

Prognostic Significance ◽

Disease Free Survival ◽

Pediatric Brain Tumors ◽

Normal Brain ◽

Diffuse Glioma ◽

Expression Levels ◽

Treatment Models ◽

New Treatment

Introduction: The noncoding RNAs (ncRNAs) play a role in biological processes of various cancers including gliomas. The majority of these transcripts are uniquely expressed in differentiated tissues or specific glioma types. Pediatric oligodendroglioma (POG) is a rare subtype of diffuse glioma and accounts for <1% of pediatric brain tumors. Because histologically POG resembles adult OG, the same treatment is applied as adults. However, the significance in predicting outcomes in POG patients is unclear. In this study, we aimed to investigate the prognostic significance of expression profiles of microRNA (miRNA) and long noncoding RNA (LncRNA) in POGs. Methods: We investigated the levels of 13 known miRNAs and 6 LncRNAs in tumor samples from 9 patients with primary POG by using RT-PCR and analyzed their association with outcomes. Results: The expression levels of miR-21, miR-106a, miR-10b, and LncRNA NEAT1 were higher, and the expression level of miR-143 was lower in POG tissues compared with normal brain tissues (p = 0.006, p = 0.032, p = 0.034, p = 0.002, and p = 0.001, respectively). High levels of NEAT1 and low expression of miR-143 were associated with decreased probability of short disease-free survival (p = 0.018 and p = 0.022, respectively). Discussion: NEAT1 and miR-143 levels could serve as reciprocal prognostic predictors of disease progression in patients with POG. New treatment models to regulate the expression levels of NEAT1 and miR-143 will bring a new approach to the therapy of POG.

Download Full-text

Prognostic Effect of Long Noncoding RNA NEAT1 Expression Depends on p53 Mutation Status in Cancer

Journal of Oncology ◽

10.1155/2019/4368068 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Masashi Idogawa ◽

Hiroshi Nakase ◽

Yasushi Sasaki ◽

Takashi Tokino

Keyword(s):

Noncoding Rna ◽

Suppressive Effect ◽

Good Prognosis ◽

P53 Mutation ◽

Wild Type ◽

Mutation Status ◽

Prognostic Effect ◽

Tumor Suppressive Function ◽

Cancer Tissues ◽

Lncrna Neat1

Recently, many studies have revealed that long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes. Our previous study reported that lncRNA NEAT1 is a direct transcriptional target of p53. NEAT1 is an essential component of paraspeckles, which have recently been identified as a novel type of nuclear compartment. Although our previous findings indicate that NEAT1 induction contributes to the tumor-suppressor function of p53, the role of NEAT1 in cancer is still controversial. In this study, we comprehensively analyzed the relationship between NEAT1 expression and p53 mutation status. Interestingly, survival analysis based on NEAT1 expression in several cancer tissues revealed that the p53 wild-type group with high NEAT1 expression had a good prognosis, while poor prognosis or no correlation between NEAT1 expression and survival was observed in the p53-mutated group. These results demonstrate that the tumor-suppressive effect of NEAT1 depends on p53 function and is consistent with our previous report showing that NEAT1 supports the tumor-suppressive function of p53. Specifically, NEAT1 seems to play a tumor-suppressive role only in the presence of wild-type p53. These results provide important clues to the roles of NEAT1 in cancer.

Download Full-text

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen

Scientific Reports ◽

10.1038/s41598-021-88120-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marta Libura ◽

Emilia Bialopiotrowicz ◽

Sebastian Giebel ◽

Agnieszka Wierzbowska ◽

Gail J. Roboz ◽

...

Keyword(s):

Myeloid Leukemia ◽

Prognostic Significance ◽

Normal Karyotype ◽

Wild Type ◽

Dna Hypermethylation ◽

Isocitrate Dehydrogenase 1 ◽

Mutation Status ◽

Group 4 ◽

Induction Regimen ◽

Favorable Prognostic Factor

AbstractMutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.

Download Full-text

Loss of BCAT1 Expression is a Sensitive Marker for IDH-Mutant Diffuse Glioma

Neurosurgery ◽

10.1093/neuros/nyy338 ◽

2018 ◽

Vol 85 (3) ◽

pp. 335-342

Author(s):

Yen-Ying Chen ◽

Hsiang-Ling Ho ◽

Shih-Chieh Lin ◽

Chih-Yi Hsu ◽

Donald Ming-Tak Ho

Keyword(s):

Dna Sequencing ◽

Prognostic Significance ◽

Surrogate Marker ◽

Cost Effective ◽

Mutation Rates ◽

Diffuse Glioma ◽

Idh Mutation ◽

Idh1 R132h ◽

Idh Mutations ◽

Mutant Idh1

Abstract BACKGROUND IDH mutation is an important prognostic factor of diffuse astrocytomas. Although the majority of IDH mutations could be identified by immunohistochemical (IHC) stain for R132H-mutant IDH1, DNA sequencing would be required for IHC negative cases to determine their IDH mutation status. This approach is not cost-effective for tumors with low IDH mutation rates. OBJECTIVE To investigate whether BCAT1 could be used as a surrogate marker for IDH mutations, because BCAT1 is an enzyme related to IDH genes. METHODS A group of 120 anaplastic astrocytomas were immunostained for BCAT1, ATRX, and R132H-mutant IDH1. Staining results correlated with the results of DNA sequencing of IDH1/IDH2. RESULTS DNA sequencing showed IDH1/2 mutations in 50.8% of cases of which 73.8% had IDH1 R132H mutation. Several IDH1 noncodon 132 mutations, ie, G97D, S122N, G123E, I130K, and G131S, which had uncertain prognostic significance, were identified. IHC stain for R132H-mutant IDH1 identified 93.3% of IDH1 R132H mutations and 70.5% of all IDH mutations. BCAT1 loss was seen in 65.8% of cases, its sensitivity to identify IDH mutations was 96.7%. The sensitivity reached 100% for IDH1 codon 132 and IDH2 codon 172 mutations. CONCLUSION Positive BCAT1 stain could be used to exclude diffuse gliomas with IDH1 codon 132 and IDH2 codon 172 mutations. Selecting cases with negative BCAT1 and R132H-mutant IDH1 staining for DNA sequencing of IDH1/2 genes could improve the cost-effectiveness of detecting IDH mutations particularly in tumors with low IDH mutation rates, and confine the need of 1p/19q assay in IDH-mutant tumors.

Download Full-text

Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling

mBio ◽

10.1128/mbio.01190-20 ◽

2020 ◽

Vol 11 (3) ◽

Cited By ~ 2

Author(s):

Surendra Sharma ◽

Karl Munger

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Tumor Suppressor ◽

Cancer Cells ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Wild Type ◽

Hpv E6 ◽

Cervical Cancer Cells ◽

Transcriptional Target

ABSTRACT Tumor cells overcome the cytostatic and cytotoxic restraints of TP53 tumor suppressor signaling through a variety of mechanisms. High-risk human papillomavirus (HPV)-positive tumor cells retain wild-type TP53 because the HPV E6/UBE3A ubiquitin ligase complex targets TP53 for proteasomal degradation. While restoration of TP53 in tumor cells holds great promise for cancer therapy, attempts to functionally restore the dormant TP53 tumor suppressor in HPV-positive cancer cells by inhibiting the HPV E6/UBE3A ubiquitin ligase complex have not yet been successful. The damage-induced long noncoding RNA, DINO (DINOL), is a TP53 transcriptional target that has been reported to bind to and stabilize TP53, thereby amplifying TP53 signaling. We show that HPV-positive cervical carcinoma cells contain low levels of DINO because of HPV E6/UBE3A-mediated TP53 degradation. Acute DINO expression overrides HPV16 E6/UBE3A-mediated TP53 degradation, causing TP53 stabilization and increased expression of TP53 transcriptional target genes. This causes a marked sensitization to chemotherapy agents and renders cells vulnerable to metabolic stress. Acute DINO expression in HPV-positive cervical cancer cells induces hallmarks of DNA damage response signaling, and TP53 activation involves ATM/CHK2 signaling. DINO upregulation in response to DNA damage is independent of ATM/CHK2 and can occur in cancer cells that express mutant TP53. IMPORTANCE Functional restoration of the TP53 tumor suppressor holds great promise for anticancer therapy. Current strategies are focused on modulating TP53 regulatory proteins. Long noncoding RNAs (lncRNAs) have emerged as important regulators of TP53 as well as modulators of downstream tumor-suppressive transcriptional responses. Unlike many other cancer types, human papillomavirus (HPV)-positive cancer cells retain wild-type TP53 that is rendered dysfunctional by the viral E6 protein. We show that acute expression of the damage-induced long noncoding RNA, DINO, a known TP53 transcriptional target and functional modulator, causes TP53 reactivation in HPV-positive cervical cancer cells. This causes increased vulnerability to standard chemotherapeutics as well as biguanide compounds that cause metabolic stress. Hence, strategies that target DINO may be useful for restoring TP53 tumor suppressor activity in HPV-positive cancers and other tumor types that retain wild-type TP53.

Download Full-text

Expression of the long noncoding RNA DINO in HPV positive cervical cancer cells reactivates the dormant TP53 tumor suppressor through ATM/CHK2 signaling

10.1101/2020.05.08.085555 ◽

2020 ◽

Author(s):

Surendra Sharma ◽

Karl Munger

Keyword(s):

Cervical Cancer ◽

Tumor Suppressor ◽

Cancer Cells ◽

Tumor Cells ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Wild Type ◽

Hpv E6 ◽

Cervical Cancer Cells ◽

Transcriptional Target

ABSTRACTTumor cells overcome the cytostatic and cytotoxic restraints of TP53 tumor suppressor signaling through a variety of mechanisms. High-risk human papillomavirus (HPV) positive tumor cells retain wild type TP53 because the HPV E6/UBE3A ubiquitin ligase complex targets TP53 for proteasomal degradation. While restoration of TP53 in tumor cells holds great promise for cancer therapy, attempts to functionally restore the dormant TP53 tumor suppressor in HPV positive cancer cells by inhibiting the HPV E6/UBE3A ubiquitin ligase complex have not yet been successful. The Damage Induced long noncoding RNA, DINO, (DINOL) is a TP53 transcriptional target that has been reported to bind to and stabilize TP53, thereby amplifying TP53 signaling. We show that HPV positive cervical carcinoma cells contain low levels of DINO because of HPV E6/UBE3A mediated TP53 degradation. Acute DINO expression overrides HPV16 E6/UBE3A mediated TP53 degradation, causing TP53 stabilization and increased expression of TP53 transcriptional target genes. This causes a marked sensitization to chemotherapy agents and renders cells vulnerable to metabolic stress. Acute DINO expression in HPV positive cervical cancer cells induces hallmarks of DNA damage response signaling and TP53 activation involves ATM/CHK2 signaling. DINO upregulation in response to DNA damage is independent of ATM/CHK2 and can occur in cancer cells that express mutant TP53.IMPORTANCEFunctional restoration of the TP53 tumor suppressor holds great promise for anti-cancer therapy. Current strategies are focused on modulating TP53 regulatory proteins. Long noncoding RNAs (lncRNAs) have emerged as important regulators of TP53 as well as modulators of downstream tumor suppressive transcriptional responses. Unlike many other cancer types, human papillomavirus (HPV) positive cancer cells retain wild type TP53 that is rendered dysfunctional by the viral E6 protein. We show that acute expression of the Damage Induced long Noncoding RNA, DINO, a known TP53 transcriptional target and functional modulator, causes TP53 reactivation in HPV positive cervical cancer cells. This causes increased vulnerability to standard chemotherapeutics as well as biguanide compounds that cause metabolic stress. Hence, strategies that target DINO may be useful for restoring TP53 tumor suppressor activity in HPV positive cancers and other tumor types that retain wild type TP53.

Download Full-text

Clinicopathological and prognostic significance of long noncoding RNA MALAT1 in human cancers: a review and meta-analysis

Cancer Cell International ◽

10.1186/s12935-018-0606-z ◽

2018 ◽

Vol 18 (1) ◽

Cited By ~ 8

Author(s):

Juan Li ◽

Zhigang Cui ◽

Hang Li ◽

Xiaoting Lv ◽

Min Gao ◽

...

Keyword(s):

Long Noncoding Rna ◽

Noncoding Rna ◽

Meta Analysis ◽

Prognostic Significance ◽

Human Cancers

Download Full-text

Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting

Journal of Neurosurgery ◽

10.3171/2016.10.jns161793 ◽

2018 ◽

Vol 128 (2) ◽

pp. 391-398 ◽

Cited By ~ 31

Author(s):

Anna Tietze ◽

Changho Choi ◽

Bruce Mickey ◽

Elizabeth A. Maher ◽

Benedicte Parm Ulhøi ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Isocitrate Dehydrogenase ◽

Prognostic Significance ◽

Resonance Spectroscopy ◽

Idh Mutation ◽

Imaging Protocol ◽

Mutation Status ◽

Idh Mutations ◽

Cerebral Gliomas

OBJECTIVEMutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme.METHODSBy extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol. In 30 of 35 patients for whom this revised protocol was used the lesions were subsequently diagnosed histologically as gliomas. Of the remaining 5 patients, 1 had a gangliocytoma, 1 had a primary CNS lymphoma, and 3 had nonneoplastic lesions. Immunohistochemistry and/or polymerase chain reaction were used to detect the presence of IDH mutations in the glioma tissue resected.RESULTSIn vivo MRS for 2HG correctly identified the IDH mutational status in 88.6% of patients. The sensitivity and specificity was 89.5% and 81.3%, respectively, when using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors. Two glioblastomas that had elevated 2HG levels did not have detectable IDH mutations, and in 2 IDH-mutated gliomas 2HG was not reliably detectable.CONCLUSIONSThe noninvasive determination of the IDH mutation status of a presumed glioma by means of MRS may be incorporated into a routine diagnostic imaging protocol and can be used to obtain additional information for patient care.

Download Full-text