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Genomic analysis of primary and recurrent gliomas reveals clinical outcome related molecular features.

ABSTRACT: Tremendous efforts have been made to explore biomarkers for classification and grading on gliomas. The goal of this study was to identify more molecular features that are associated with clinical outcomes by comparing the genomic profiles of primary and recurrent gliomas and determine potential recurrence leading factors that are significantly enriched in relapse tumors. Hybrid capture based next generation sequencing (NGS) analysis was performed on 64 primary and 17 recurrent glioma biopsies. Copy number variation (CNV) was more frequent in recurrent tumors and CDKN2A/B loss was significantly enriched. In addition, overall mutations in cell cycle pathway are more common in relapse tumors. The patterns of gene sets, including IDH1/TERT and IDH1/TP53 exhibited significant difference between the groups. Survival analysis uncovered the worse disease-free survival (DFS) and overall survival (OS) associated with altered copy number and excessive activation of CELL CYCLE pathway. High Tumor Mutation Burden (TMB) was also a biomarker with great potential for poor prognosis. The assessment of genomic characteristics in primary versus recurrent gliomas aids the discovery of potential predictive biomarkers. The prognostic value of TMB in gliomas was raised for the first time.

SUBMITTER: Zhang L

PROVIDER: S-EPMC6831607 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genomic analysis of primary and recurrent gliomas reveals clinical outcome related molecular features.

Zhang Longbo L Liu Zhiqiang Z Li Jin J Huang Tianxiang T Wang Ying Y Chang Lianpeng L Zheng Wenjie W Ma Yujie Y Chen Fenghua F Gong Xuan X Yuan Qianying Q Teaw Shannon S Fang Xinqi X Song Tao T Huo Lei L Li Xi X Xia Xuefeng X Liu Zhixiong Z Wu Jun J

Scientific reports 20191105 1

Tremendous efforts have been made to explore biomarkers for classification and grading on gliomas. The goal of this study was to identify more molecular features that are associated with clinical outcomes by comparing the genomic profiles of primary and recurrent gliomas and determine potential recurrence leading factors that are significantly enriched in relapse tumors. Hybrid capture based next generation sequencing (NGS) analysis was performed on 64 primary and 17 recurrent glioma biopsies. C ...[more]

PMID: 31690770

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Project description:ObjectiveTo study the expression of IL13RA2 in gliomas and to analyze its correlation with clinicopathological/molecular features, immune cell infiltration and prognostic significance.MethodsmRNA expression data for IL13RA2 were downloaded and analyzed from two open access datasets (TCGA & CGGA). IL13RA2 protein expression was examined by immunohistochemistry. The association between IL13RA2 and important clinicopathological/molecular markers was examined using χ2 and Spearman correlation tests. The TIMER tool was used to evaluate the correlation of IL13RA2 with multiple intra-tumoral immune cell types in glioma. Kaplan-Meier test and multivariate Cox analyses were applied to evaluate the prognosis.ResultsOut of the 297 glioma tissues and 20 normal brain tissues in our cohort, IL13RA2 protein was highly expressed in 115 glioma tissues (115/297, 38.7%), but no expression was detected in normal brain tissues (0/20, 0%). The expression of IL13RA2 was significantly higher in GBMs (P<0.001). More than half of GBMs (68/132, 51.5%) were high expression of IL13RA2 protein, especially GBM patients with IDH wild-type and TERT promoter mutated (60/78, 76.9%). Moreover, 11/13 (84.6%) diffuse midline gliomas and 31/51 (64.7%) IDH wild-type LGGs also highly expressed IL13RA2 in our cohorts. Chi-square test showed that the expression of IL13RA2 was correlated with patient age, WHO grade, Ki67 index, IDH status, TERT promoter status and immune cell infiltration. Additionally, IL13RA2 was strongly associated with patients' OS and served as a negative prognostic marker in infiltrating gliomas.ConclusionIL13RA2 was high expression in some glioma subtypes, and significantly correlated with poor prognosis. Based on its role in CAR-T therapy, it might act as an extremely important and specific therapeutic target for human malignant gliomas, especially in IDH wild-type LGG, "IDH wild-type and TERT promoter mutated" GBM and H3K27M-mutated diffuse midline glioma, and improve the clinical outcomes of these patients.

Project description:BackgroundSerous borderline ovarian tumour (SBOT) is the most common type of BOT. Fertility sparing surgery (FSS) is an option for patients with SBOT, though it may increase the risk of recurrence. The clinical and molecular features of its recurrence are important and need to be investigated in detail.MethodsAn internal cohort of 319 patients with SBOT was collected from Aug 1, 2009 to July 31, 2019 from the Obstetrics and Gynecology Hospital of Fudan University in China. An external cohort of 100 patients with SBOT was collected from Aug 1, 2009 to Nov 30, 2019 from the Shandong Provincial Hospital in China. The risk factors for the recurrence were identified by multivariate cox analysis. Several computational methods were tested to establish a prediction tool for recurrence. Whole genome sequencing, RNA-seq, metabolomics and lipidomics were used to understand the molecular characteristics of the recurrence of SBOT.FindingsFive factors were significantly correlated with SBOT recurrence in a Han population: micropapillary pattern, advanced stage, FSS, microinvasion, and lymph node invasion. A random forest-based online recurrence prediction tool was established and validated using an internal cohort and an independent external cohort for patients with SBOT. The multi-omics analysis on the original SBOT samples revealed that recurrence is related to metabolic regulation of immunological suppression.InterpretationOur study identified several important clinical and molecular features of recurrent SBOT. The prediction tool we established could help physicians to estimate the prognosis of patients with SBOT. These findings will contribute to the development of personalised and targeted therapies to improve prognosis.FundingJL was funded by MOST 2020YFA0803600, 2018YFA0801300, NSFC 32071138, and SKLGE-2118 to Jin Li; JY was funded by the Initial Project for Young and Middle-aged Medical Talents of Wuhan City, Hubei Province ([2014] 41); HH was funded by MOST 2019YFA0801900 and 2020YF1402600 to He Huang; JS was funded by NSFC 22,104,080; CG was funded by Natural Science Foundation of Shanghai 20ZR1408800 and NSFC82171633; BL was funded by Natural Science Foundation of Shanghai 19ZR1406800.

Dataset Information

Genomic analysis of primary and recurrent gliomas reveals clinical outcome related molecular features.

Publications

Genomic analysis of primary and recurrent gliomas reveals clinical outcome related molecular features.

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