Yinyan Wang

IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry.

Background The relative contribution of isocitrate dehydrogenase mutations (mIDH) and O6-methylguanine-DNA methyltransferase promoter methylation (methMGMT) as biomarkers in glioblastoma remain poorly understood. Methods We investigated the association between methMGMT and mIDH with progression free survival and overall survival in a prospectively collected molecular registry of 274 glioblastoma patients. Results For glioblastoma patients who underwent Temozolomide and Radiation Therapy, OS and PFS was most favorable for those with tumors harboring both mIDH and methMGMT (median OS: 35.8 mo, median PFS: 27.5 mo); patients afflicted glioblastomas with either mIDH or methMGMT exhibited intermediate OS and PFS (mOS: 36 and 17.1 mo; mPFS: 12.2 mo and 9.9 mo, respectively); poorest OS and PFS was observed in wild type IDH1 (wtIDH1) glioblastomas that were MGMT promoter unmethylated (mOS: 15 mo, mPFS: 9.7 mo). For patients with wtIDH glioblastomas, TMZ+RT was associated with improved OS and PFS relative to patients treated with RT (OS: 15.4 mo v 9.6 mo, p < 0.001; PFS: 9.9 mo v 6.5 mo, p < 0.001). While TMZ+RT and RT treated mIDH patients exhibited improved overall survival relative to those with wtIDH, there were no differences between the TMZ+RT or RT group. These results suggest that mIDH1 conferred resistance to TMZ. Supporting this hypothesis, exogenous expression of mIDH1 in independent astrocytoma/glioblastoma lines resulted in a 3–10 fold increase in TMZ resistance after long-term passage. Conclusion Our study demonstrates IDH mutation and MGMT promoter methylation status independently associate with favorable outcome in TMZ+RT treated glioblastoma patients. However, these biomarkers differentially impact clinical TMZ response.

Clinical and molecular genetic factors affecting postoperative seizure control of 183 Chinese adult patients with low-grade gliomas.

Background and purpose:  Seizures are a common symptom of patients with primary brain tumors, particularly low‐grade gliomas (LGGs). Poor seizure control after surgery has a great adverse impact on quality of life in these patients. The present study aimed to identify clinical and molecular genetic factors that influence postoperative seizure control.

Identification of a 6-Cytokine Prognostic Signature in Patients with Primary Glioblastoma Harboring M2 Microglia/Macrophage Phenotype Relevance

Background Glioblastomas (GBM) are comprised of a heterogeneous population of tumor cells, immune cells, and extracellular matrix. Interactions among these different cell types and pro-/anti-inflammatory cytokines may promote tumor development and progression. Aims The objective of this study was to develop a cytokine-related gene signature to improve outcome prediction for patients with primary GBM. Methods Here, we used Cox regression and risk-score analysis to develop a cytokine-related gene signature in primary GBMs from the whole transcriptome sequencing profile of the Chinese Glioma Genome Atlas (CGGA) database (n=105). We also examined differences in immune cell phenotype and immune factor expression between the high-risk and low-risk groups. Results Cytokine-related genes were ranked based on their ability to predict survival in the CGGA database. The six genes showing the strongest predictive value were CXCL10, IL17R, CCR2, IL17B, IL10RB, and CCL2. Patients with a high-risk score had poor overall survival and progression-free survival. Additionally, the high-risk group was characterized by increased mRNA expression of M2 microglia/macrophage markers and elevated levels of IL10 and TGFβ1. Conclusion The six cytokine-related gene signature is sufficient to predict survival and to identify a subgroup of primary GBM exhibiting the M2 cell phenotype.

Classification based on mutations of TERT promoter and IDH characterizes subtypes in grade II/III gliomas

BACKGROUND Grade II and III gliomas have variable clinical behaviors, showing the distinct molecular genetic alterations from glioblastoma (GBM), many of which eventually transform into more aggressive tumors. Since the classifications of grade II/III gliomas based on the genetic alterations have been recently emerging, it is now a trend to include molecular data into the standard diagnostic algorithm of glioma. METHODS Here we sequenced TERT promoter mutational status (TERTp-mut) in the DNA of 377 grade II/III gliomas and analyzed the clinical factors, molecular aberrations, and transcriptome profiles. RESULTS We found that TERTp-mut occurred in 145 of 377 grade II and III gliomas (38.5%), mutually exclusive with a TP53 mutation (TP53-mut; P < .001) and coincident with a 1p/19q co-deletion (P = .002). TERTp-mut was an independent predictive factor of a good prognosis in all patients (P = .048). It has been an independent factor associated with a good outcome in the IDH mutation (IDH-mut) subgroup (P = .018), but it has also been associated with a poor outcome in the IDH wild-type (IDH-wt) subgroup (P = .049). Combining TERTp-mut and IDH-mut allowed the grade II/III malignancies to be reclassified into IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt. 1p/19q co-deletion, TP53-muts, Ki-67 expression differences, and p-MET expression differences characterized IDH-mut/TERTp-mut, IDH-mut only, TERTp-mut only, and IDH-wt/TERTp-wt subtypes, respectively. CONCLUSIONS Our results showed that TERTp-mut combined with IDH-mut allowed simple classification of grade II/III gliomas for stratifying patients and clarifying diagnostic accuracy by supplementing standard histopathological criteria.

IDH1/2 mutation is associated with seizure as an initial symptom in low-grade glioma: A report of 311 Chinese adult glioma patients.

BACKGROUND Seizure commonly presents as an initial symptom and plays an important role in the clinical presentation and quality of life of patients with low-grade glioma (LGG). To date, the mechanism and genetic alterations underlying tumor-related seizures in LGG remain to be fully elucidated. Both isocitrate dehydrogenase 1/2 (IDH1/2) mutation and seizure frequently occur in patients with LGG. We set out to investigate the potential relationship between IDH1/2 mutation and presentation of seizure preoperatively, and observe whether or not IDH1/2 mutation influences seizure control postoperatively. METHODS A total of 311 adult patients with LGG were enrolled in our study with both clinical data and IDH1/2 mutation data available. IDH1/2 mutation was detected directly by pyro-sequencing. The chi-squared test was performed to determine whether the IDH1/2 mutation has any relevance to seizure onset and to evaluate the potential impact that IDH1/2 mutation may exert on seizure control postoperatively. RESULTS Seizure presented as an initial symptom in 71.4% (222/311) of patients with LGG, among which 189 patients were detected to bear IDH1/2 mutation in their tumors (P=0.035, chi-squared test). However, IDH1/2 mutation does not seem to contribute to the seizure control postoperatively (P=0.350 and 0.577 for the 6- and 12-month follow-up, respectively, chi-squared test). CONCLUSIONS IDH1/2 mutation occurs more frequently in LGG patients with seizure as an initial symptom, suggesting a potential relationship between this genetic phenotype and clinical seizure presentation. IDH1/2 mutation shows no prognostic value for postoperative seizure control.

Direct evidence of the left caudate’s role in bilingual control: An intra-operative electrical stimulation study

Bilinguals need control mechanisms in order to switch between languages in different communication contexts (Green, 1998, Bilingualism: Language and Cognition, 1; Price, Green, & von Studnitz, 1999, Brain, 122). There has been neural evidence showing competition to control output in L2 vs. L1 in both cortical and sub-cortical areas, when language selection is carried out (Abutalebi & Green, 2007, Journal of Neurolinguistics, 20). Here we use intra-operative direct electrical stimulation to demonstrate that the head of the left caudate is critical not only in language switching tasks but other control tasks. A bilingual Chinese-English patient was instructed to perform both language switching and switching in color-shape naming tasks during awake glioma surgery. When stimulation was applied on the left caudate, failures or difficulties in both language switching and color-shape naming were observed, with the effects greater on language switching. Stimulation to neighboring brain regions either did not affect performance or generated mild problems specific to language switching. The results provide direct evidence of the necessary role of the left caudate in language control.

Isocitrate dehydrogenase 1 (IDH1) mutation-specific microRNA signature predicts favorable prognosis in glioblastoma patients with IDH1 wild type

BackgroundTo date, no prognostic microRNAs (miRNAs) for isocitrate dehydrogenase 1 (IDH1) wild-type glioblastoma multiformes (GBM) have been reported. The aim of the present study was to identify a miRNA signature of prognostic value for IDH1 wild-type GBM patients using miRNA expression dataset from the The Cancer Genome Atlas (TCGA).MethodsDifferential expression profiling analysis of miRNAs was performed on samples from 187 GBM patients, comprising 17 mutant-type IDH1 and 170 wild-type IDH1 samples.ResultsA 23-micoRNA signature which was specific to the IDH1 mutation was revealed. Survival data was available for 140 of the GBM patients with wild-type IDH1. Using these data, the samples were characterized as high-risk or low-risk group according to the ranked protective scores for each of the 23 miRNAs in the 23-miRNA signature. Then, the 23 IDH1 mutation-specific miRNAs were classified as risky group and protective group miRNAs based on the significance analysis of microarrays d-score (SAM d-value) (positive value or negative value). The risky group miRNAs were found to be expressed more in the high-risk samples while the protective group miRNAs were expressed more in the low-risk samples. Patients with high protective scores had longer survival times than those with low protective scores.ConclusionThese findings show that IDH1 mutation-specific miRNA signature is a marker for favorable prognosis in primary GBM patients with the IDH1 wild type.

MR Evaluation of Sinonasal Angiomatous Polyp

BACKGROUND AND PURPOSE: SAP is a rare lesion of the sinonasal cavity, which may be misdiagnosed as a benign or malignant neoplasm. The purpose of our study was to comprehensively evaluate the MR imaging features of SAP. MATERIALS AND METHODS: Forty patients with SAP confirmed pathologically were retrospectively reviewed. Of the 40 patients undergoing MR imaging, 39 had postcontrast T1WI; 30, DCE MR imaging; and 17, DWI. The image features assessed included the location, shape, margin, size, signal intensity, and enhancement pattern on DCE MR imaging and ADC maps. RESULTS: All 40 SAPs originated from the maxillary sinus, but the lesions frequently extended into the ipsilateral nasal cavity (38/40), toward the choana (19/40), and into the nasopharynx (8/40). The lesions demonstrated hypointensity on T1WI and heterogenous hyperintensity on T2WI. All 40 lesions showed a peripheral hypointense rim on T2WI. Postcontrast MR imaging revealed marked heterogeneous nodular and patchy enhancement. Progressive enhancement was found on DCE MR imaging in 30 cases. The TIC showed a steady enhancement pattern in 3 cases, a rapidly enhancing and slow washout pattern in 6 cases, and a rapidly enhancing and rapid washout pattern in 21 cases. On DWI, the mean ADC value was (1.40 ± 0.20) × 10−3 mm2/s. CONCLUSIONS: Distinctive features of SAP on conventional MR imaging include internal heterogeneous hyperintensity and a peripheral hypointense rim on T2WI, as well as strong nodular and patchy enhancement on postcontrast MR images. The progressive enhancement on DCE MR imaging can also suggest the diagnosis.

Correlation of preoperative seizures with clinicopathological factors and prognosis in anaplastic gliomas: A report of 198 patients from China

PURPOSE Seizures are a common manifestation of many diseases and play an important role in the clinical presentation and quality of life (QOL) in patients with gliomas. The purpose of the present study was to investigate the possible correlation between tumor-related seizures and clinicopathological factors that influence preoperative seizure characteristics and relevant survival outcomes. METHODS We retrospectively investigated the correlation of preoperative seizures with clinicopathological factors and prognosis in a cohort of 198 Chinese patients with anaplastic gliomas. Univariate and multivariate logistic regression analyses were used to identify factors associated with preoperative seizures. Survival function curves were calculated using the Kaplan-Meier method. RESULTS Of the 198 patients, 68 (34.3%) patients had preoperative seizures. Among the patients with seizures, 26 (38.2%) had generalized seizures, 38 (55.9%) had simple partial seizures, and four (5.9%) complex seizures. There was a higher proportion of epidermal growth factor receptor (EGFR) amplification, frontal lobe involvement, left cerebral hemisphere involvement, and lower Ki-67 expression in patients with preoperative seizures in both univariate and multivariate analyses. Patients with preoperative seizures had a longer overall survival (OS) time compared with those without (median: 1924 days vs. 923 days, P=0.048). CONCLUSION The current study updates existing information on tumor-related seizures and clinicopathological factors in anaplastic gliomas, and suggests two putative biomarkers for preoperative seizures; Ki-67 expression and EGFR amplification. These factors may provide insights for developing effective treatment strategies aimed at prolonging patient survival.

SOCS3 promoter hypermethylation is a favorable prognosticator and a novel indicator for G-CIMP-positive GBM patients.

Background Hypermethylation of the suppressor of cytokine signaling 3(SOCS3) promoter has been reported to predict a poor prognosis in several cancers including glioblstoma multiforme (GBM). We explored the function of SOCS3 promoter hypermethylation in GBM cohorts, including analysis of the CpG island methylator phenotype (CIMP), when a large number of gene loci are simultaneously hypermethylated. Methods A whole genome promoter methylation profile was performed in a cohort of 33 GBM samples, with 13 long-term survivors (LTS; overall survival ≥ 18 months) and 20 short-term survivors (STS; overall survival ≤ 9 months). The SOCS3 promoter methylation status was compared between the two groups. In addition, we investigated the relationship of SOCS3 promoter methylation and G-CIMP status. Results Interestingly, in our present study, we found that SOCS3 promoter methylation was statistically significantly higher in the 13 LTS than that in the 20 STS. Furthermore, high SOCS3 promoter methylation detected via pyro-sequencing predicted a better prognosis in an independent cohort containing 62 GBM patients. This correlation was validated by the dataset from the Cancer Genome Atlas(TCGA) and the Chinese Cancer Genome Atlas(CGGA). In addition, we found that hypermethylation of the SOCS3 promoter was tightly associated with the G-CIMP-positive GBM patients. Conclusions Using a total of 359 clinical samples, we demonstrate that SOCS3 promoter hypermethylation status has a favorable prognostic value in GBM patients because of whole genome methylation status. Particularly, the hypermethylation of the SOCS3 promoter indicates positive G-CIMP status.