scholarly journals High Frequency of PDGFRA and MUC Family Gene Mutations in Diffuse Hemispheric Glioma, H3 G34-mutant: A Glimmer of Hope?

2021 ◽  
Author(s):  
Wanming Hu ◽  
Hao Duan ◽  
Sheng Zhong ◽  
Jing Zeng ◽  
Yonggao Mou
Keyword(s):  
Targeted Therapy ◽  
Rna Sequencing ◽  
High Frequency ◽  
High Grade Glioma ◽  
Chinese Patients ◽  
Molecular Characteristics ◽  
High Grade ◽  
Rna Seq ◽  
Immune Infiltration ◽  
Genome Atlas

Abstract BackgroundDiffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA). MethodsHematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data.ResultsWES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months. ConclusionsOur results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs.

scholarly journals CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii34
Author(s):  
Macarena De La Fuente ◽  
Tulay Koru-Sengul ◽  
Deborah Heros ◽  
Feng Miao ◽  
Alain Fernandez Marrero ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Rna Sequencing ◽  
Tumor Antigens ◽  
High Grade Glioma ◽  
Treatment Discontinuation ◽  
Sequencing Analysis ◽  
High Grade ◽  
Who Grade ◽  
Cytokine Levels ◽  
Grade 3

Abstract BACKGROUND Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells. METHODS Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel. RESULTS A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed. CONCLUSION Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.

scholarly journals EPCO-23. COMPARATIVE TRANSCRIPTOMICS TO IDENTIFY TARGETED THERAPY CANDIDATES IN HIGH GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii74-ii74
Author(s):  
Kelsey Hundley ◽  
Olena Vaske ◽  
Geoff Lyle ◽  
Katrina Learned ◽  
Holly Beale ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Targets ◽  
High Grade Glioma ◽  
Comparative Transcriptomics ◽  
Potential Candidate ◽  
High Grade ◽  
Illumina Hiseq ◽  
Li Fraumeni Syndrome ◽  
Statistical Framework ◽  
Genomic Characterization

Abstract Genomic characterization is often used for the identification of therapeutic targets in tumors. Recently, comparative transcriptomics has begun to be utilized for this purpose. In this pilot, we compare the transcriptome of a patient with recurrent high grade glioma (HGG) to our cohort to identify potential therapies. We reviewed transcriptomic profiles from patients who had resection of HGG at our institution over the past year as well as the UCSC cancer compendium. Briefly, tumor RNA was extracted from embedded tumor tissue sections with tumor cellularity higher than 20%. RNA libraries were sequenced to obtain approximately 65 million reads on an Illumina HiSeq 4000 System utilizing patterned flow cell technology. The RNA profile of a 24 male with Li-Fraumeni syndrome and recurrent HGG with leptomeningeal spread underwent comparative transcriptomics to identify targets. A Bayesian statistical framework for gene expression outlier detection was used. These comparisons allowed for the identification of genes and pathways that are significantly overexpressed. Our internal HGG cohort consisted of 44 adult patients and was evenly distributed among the 4 HGG Verhaak subtypes. Our patient of interest had druggable outlier expression in HDAC1, STAT1 and STAT2 in comparison to our internal cohort indicating vorinostat and ruxolitinib as potential therapies, respectively. We then compared our patient of interest to 12,747 patients in the cancer compendium and STAT2 expression was high but not an outlier. In comparison to 738 glioma samples, STAT1 and STAT2 were outliers but not HDAC1 again indicating ruxolitinib as a potential targeted therapy. The patient did not have outlier expression in notch transcriptional targets or immune checkpoint biomarkers when compared to all cohorts. In conclusion, comparative Transcriptomics can identify therapeutic targets in a patient with recurrent HGG even in small cohorts. In our pilot, we identified ruxolitinib as a potential candidate to treat leptomeningeal recurrence.

EPCO-07. HYBRID NEURO-GLIAL CELLULAR ARCHITECTURE IN HIGH-GRADE GLIOMA DRIVEN BY H3-G34R MUTATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi2-vi2
Author(s):  
Julie Laffy ◽  
Masashi Nomura ◽  
Chen He ◽  
Lillian Bussema ◽  
Michal Slyper ◽  
...  
Keyword(s):  
Young Adults ◽  
Rna Sequencing ◽  
Developmental Trajectories ◽  
High Grade Glioma ◽  
Cerebral Hemispheres ◽  
High Grade ◽  
Malignant Cells ◽  
Aberrant Expression ◽  
Cellular Architecture ◽  
Single Nucleus

Abstract High-grade gliomas (HGG) with histone H3.3 G34R mutation are rare intractable tumours in the cerebral hemispheres that preferentially affect adolescents and young adults, but have unknown mechanisms of neuroanatomical specificity and tumourigenesis. Here, we performed single-nucleus RNA-sequencing of twenty patient samples, encompassing twelve tumours with G34R mutation and eight H3.3 wildtype HGGs, age- and location-matched. Both classes of HGG were heterogeneous, with malignant cells in multiple states, recapitulating neural and glial developmental trajectories. G34R HGG is distinguished by lack of malignant cells in the oligodendroglial lineage, and aberrant expression of neuronal programs superimposed over cellular states, resulting in hybrid glio-neuronal malignant programs. Singe-cell barcoding supports plasticity between cellular states in HGG with multiple possible transitions. CRISPR-correction of G34R in HGG models followed by scRNA-seq supports that the G34R mutation directly drives these aberrant programs. Our study provides a framework for studying the origin and tumourigenesis of paediatric gliomas.

scholarly journals High frequency of the X-chromosome inactivation in young female patients with high-grade glioma

2013 ◽  
Vol 8 (1) ◽  
Author(s):  
Gang Li ◽  
Zhiguo Zhang ◽  
Tianbo Jin ◽  
Hongjuan Liang ◽  
Yanyang Tu ◽  
...  
Keyword(s):  
X Chromosome ◽  
High Frequency ◽  
High Grade Glioma ◽  
Young Female ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
High Grade ◽  
Female Patients

scholarly journals HGG-04. USE OF AN ADVANCED RNA-SEQ FUSION PIPELINE RESULTS IN THE TARGETED TREATMENT AND SUSTAINED CLINICAL RESPONSE OF CHILDREN WITH RECURRENT PEDIATRIC HIGH-GRADE GLIOMA

2019 ◽  
Vol 21 (Supplement_2) ◽  
pp. ii87-ii87
Author(s):  
Kallen Schwark ◽  
Amy Bruzek ◽  
Chandan Kumar-Sinha ◽  
Sylvia Escolero ◽  
Bernard Marini ◽  
...  
Keyword(s):  
Clinical Response ◽  
High Grade Glioma ◽  
Targeted Treatment ◽  
High Grade ◽  
Rna Seq ◽  
Pediatric High Grade Glioma

RNA sequencing effectively identifies gene fusions undetected by DNA sequencing in lung adenocarcinomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3052-3052
Author(s):  
Ruiying Zhao ◽  
Yuchen Han ◽  
Chan Xiang ◽  
Shengnan Chen ◽  
Jikai Zhao ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Rna Sequencing ◽  
Genomic Rearrangements ◽  
Driver Gene ◽  
Functional Domain ◽  
Gene Fusions ◽  
Rna Seq ◽  
Probe Coverage ◽  
Therapeutic Decision Making ◽  
Lung Adenocarcinomas

3052 Background: Next-generation sequencing of DNA, which can provide valid information for clinical therapeutic decision-making, has been widely used in the management of lung cancer especially adenocarcinoma. However, due to its technical limitations for detecting certain alterations such as gene rearrangement, the DNA-based sequencing (DNA-seq) may miss the actionable alteration in some cases, who would have benefited from targeted therapy. The study aimed to evaluate the capability of RNA sequencing (RNA-seq) in identifying DNA-seq undetectable gene alterations in lung adenocarcinomas. Methods: A total of 219 lung adenocarcinomas, which had no driver alteration detected by DNA-seq (OncoScreen Plus, Burning Rock Biotech) and had a max AF ≥5%, underwent capture-based RNA-seq using a custom panel (OncoRNA, Burning Rock Biotech) spanning full transcripts of 115 genes commonly involved in cancer genomic rearrangements. Furthermore, an independent cohort of 100 DNA-seq driver–negative lung adenocarcinomas were also subjected to RNA-seq with the same panel. Results: In the discovery cohort, 166/219 samples (75.8%) generated qualified RNA-seq data for subsequent analyses. RNA-seq identified 44 previously undetected alterations (26.5%), including 40 gene fusions (24.1%), 1 MET exon14 skipping variant ( METex14, 0.6%) and 3 other alternative splicing variants (1.8%). Among them, 14 (8.4%) were potential actionable alterations, consisting of METex14 and in-frame fusions containing functional domain of the driver gene (4 ROS1 fusions, 3 BRAF fusions, 2 NRG1 fusions, 2 EGFR fusions, 1 ALK fusion and 1 MET fusion). In the validation cohort, 69/100 samples (69.0%) generated qualified data. RNA-seq identified 22 DNA-seq undetected alterations (31.9%), with 7 of them being potential actionable fusions (10.1%). ROS1 fusion remained as the most common actionable alteration (n = 3), followed by ALK fusion (n = 2), EGFR fusion (n = 1) and MET fusion (n = 1). Further analyses of the two datasets revealed that lacking sufficient coverage spanning the rearrangement breakpoint in the DNA-seq panel mainly accounted for the failure of DNA-seq on detecting these fusions. This can be improved by increasing the corresponding probe coverage in the DNA-seq panel. In addition, complex genomic rearrangement at DNA level and the presence of repetitive sequence in the intronic region spanning or adjacent to the breakpoint might lead to missed calling of canonical fusions by DNA-seq. Conclusions: Targeted RNA-seq can effectively identify genomic rearrangements that are undetectable by DNA-seq and provide lung adenocarcinoma patients with more opportunities for targeted therapy. Therefore, it should be recommended for all patients, in whom DNA-seq fails to detect driver alteration.

scholarly journals A case report of targeted therapy with apatinib in a patient with recurrent high grade glioma

Medicine ◽  
2018 ◽  
Vol 97 (22) ◽  
pp. e10859 ◽  
Author(s):  
Xiuping Ding ◽  
Jujie Sun ◽  
Tingyong Fan ◽  
Baosheng Li
Keyword(s):  
Case Report ◽  
Targeted Therapy ◽  
High Grade Glioma ◽  
High Grade

scholarly journals PO-334 Identification of shared lineage programs across high-grade glioma subtypes by single-cell RNA-seq

2018 ◽  
Author(s):  
S Muller ◽  
E Di Lullo ◽  
A Bhaduri ◽  
M Aghi ◽  
AR Kriegstein ◽  
...  
Keyword(s):  
Single Cell ◽  
High Grade Glioma ◽  
High Grade ◽  
Rna Seq

scholarly journals Possible Human Papillomavirus 38 Contamination of Endometrial Cancer RNA Sequencing Samples in The Cancer Genome Atlas Database

2015 ◽  
Vol 89 (17) ◽  
pp. 8967-8973 ◽  
Author(s):  
Majid Kazemian ◽  
Min Ren ◽  
Jian-Xin Lin ◽  
Wei Liao ◽  
Rosanne Spolski ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Human Papillomavirus ◽  
Rna Sequencing ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Cross Contamination ◽  
Rna Seq ◽  
Cancer Genome Atlas ◽  
Genome Atlas

ABSTRACTViruses are causally associated with a number of human malignancies. In this study, we sought to identify new virus-cancer associations by searching RNA sequencing data sets from >2,000 patients, encompassing 21 cancers from The Cancer Genome Atlas (TCGA), for the presence of viral sequences. In agreement with previous studies, we found human papillomavirus 16 (HPV16) and HPV18 in oropharyngeal cancer and hepatitis B and C viruses in liver cancer. Unexpectedly, however, we found HPV38, a cutaneous form of HPV associated with skin cancer, in 32 of 168 samples from endometrial cancer. In 12 of the HPV38-positive (HPV38+) samples, we observed at least one paired read that mapped to both human and HPV38 genomes, indicative of viral integration into the host DNA, something not previously demonstrated for HPV38. The expression levels of HPV38 transcripts were relatively low, and all 32 HPV38+samples belonged to the same experimental batch of 40 samples, whereas none of the other 128 endometrial carcinoma samples were HPV38+, raising doubts about the significance of the HPV38 association. Moreover, the HPV38+samples contained the same 10 novel single nucleotide variations (SNVs), leading us to hypothesize that one patient was infected with this new isolate of HPV38, which was integrated into his/her genome and may have cross-contaminated other TCGA samples within batch 228. Based on our analysis, we propose guidelines to examine the batch effect, virus expression level, and SNVs as part of next-generation sequencing (NGS) data analysis for evaluating the significance of viral/pathogen sequences in clinical samples.IMPORTANCEHigh-throughput RNA sequencing (RNA-Seq), followed by computational analysis, has vastly accelerated the identification of viral and other pathogenic sequences in clinical samples, but cross-contamination during the processing of the samples remain a major problem that can lead to erroneous conclusions. We found HPV38 sequences specifically present in RNA-Seq samples from endometrial cancer patients from TCGA, a virus not previously associated with this type of cancer. However, multiple lines of evidence suggest possible cross-contamination in these samples, which were processed together in the same batch. Despite this potential cross-contamination, our data indicate that we have detected a new isolate of HPV38 that appears to be integrated into the human genome. We also provide general guidelines for computational detection and interpretation of pathogen-disease associations.

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