BIOM-43. GLUTAMATE RECEPTOR AND GLUTAMINE METABOLISM PROFILING BY GENE EXPRESSION ANALYSIS AMONG PATIENTS WITH HIGH GRADE GLIOMA (HGG)

Abstract BACKGROUND Glutaminolysis and excessive glutamate production are among the metabolic hallmarks of HGG. In addition to a probable role in causing seizures, autocrine stimulation of metabotropic and ionotropic (NMDA, AMPA, and kainate) receptors are capable of activating intracellular signaling pathways that are tumorigenic and contribute to drug and radiation resistance. While hints of a survival benefit from glutamate receptor targeting have occasionally emerged from the clinic, no single strategy has consistently demonstrated efficacy. Hence, we sought to characterize the magnitude of glutamate receptor overexpression and its diversity across a population of HGG patients. METHODS A set of 41 genes related to glutamate metabolism was selected from the literature. RNA gene counts for TCGA glioblastoma multiforme (N=163) and Grade 3 glioma samples (Astrocytoma=82, Oligodendroglioma=47, Oligoastrocytoma=39) were downloaded from https://portal.gdc.cancer.gov/. Annotation on subtypes and PFS values were obtained from PMID: 24120142 and 26061751. Gene expression normalization as FPKM and hierarchical clustering were performed using R-3.6.0 genes. RESULTS A heatmap with hierarchical clustering for glutamate and glutamine-related genes for the TCGA GBM and grade III glioma samples cohort was generated including colored annotation for the subtype and progression free survival. The graph shows a rough separation into two groups, with grade III gliomas and proneural samples tentatively clustering together and showing higher expression for most of the glutamate related genes. The magnitude of glutaminolysis-related gene over-expression varied significantly across the cohort suggesting a wide variety in the extent of glutamine addiction. CONCLUSION Specific glutamate receptors are commonly upregulated in HGG patients, however the heterogeneity underlying this phenomenon suggests that uniform drug strategies are unlikely to succeed in a diverse population. However, gene expression analysis has utility to identify specific glutamate receptor and glutamine profiles and to inform the treatment strategies for discrete subsets of patients using drugs that are already in the armamentarium.

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P04.05 Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma

Neuro-Oncology ◽

10.1093/neuonc/noab180.062 ◽

2021 ◽

Vol 23 (Supplement_2) ◽

pp. ii19-ii19

Author(s):

A D Maier ◽

A Meddis ◽

J Haslund-Vinding ◽

C Mirian ◽

A Areskeviciute ◽

...

Keyword(s):

Gene Expression ◽

Malignant Transformation ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Rna Expression ◽

Malignant Meningioma ◽

Who Grade ◽

Significant Difference ◽

Who Grade Iii ◽

Grade Iii

Abstract BACKGROUND Malignant meningiomas comprise 2–5% of all meningiomas. The process of malignant transformation when benign meningiomas (WHO grade I-II) become malignant (WHO grade III) has not previously been investigated in sequential tumour surgeries. Upregulation of FOXM1 expression and DREAM-complex repression have shown phenotypical subgroups correlating with WHO grade and aggressiveness. We investigated the RNA expression of 30 genes central to meningioma biology and 770 genes involved in neuroinflammatory pathways in primary and secondary malignant meningioma patients who underwent one to several operations. MATERIALS AND METHODS We identified a cohort of consecutive malignant meningioma patients treated at Rigshospitalet, Copenhagen from 2000–2020 (n=51) and gathered their malignant tumours and previous WHO grade I/II tumours. The malignant cohort (MC) was counter matched with a benign cohort (BC) where patients had no recurrences during follow-up. RNA expression signatures from 140 samples from the MC and 51 samples from the BC were analysed with the Nanostring Neuroinflammation panel customized with 30 genes known to be relevant in meningioma phenotypes. RESULTS 49% of MC patients had a previous grade I/II meningioma making them secondary malignant meningioma patients. Progression-free survival calculated from first malignant surgery to first recurrence or death showed no significant difference in the primary vs. secondary patients. Preliminary results of single-gene analysis of MC tumours showed FOXM1, MYBL2, TOP2A, BIRC5 expression was higher in WHO grade III samples. Gene-expression signatures in the individual patients and gene ontology enrichment analyses are in process. CONCLUSIONS FOXM1, MYBL2, TOP2A, BIRC5 RNA expression levels seem to rise during malignant progression across patients. Gene-expression analysis using the Nanostring technology is feasible and a potentially powerful tool to distinguish meningiomas prone to malignant transformation from truly benign meningiomas.

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OTEH-3. Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.042 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii10-ii11

Author(s):

Andrea Daniela Maier ◽

Alessandra Meddis ◽

Jeppe Haslund-Vinding ◽

Christian Mirian ◽

Ausrine Areskeviciute ◽

...

Keyword(s):

Gene Expression ◽

Malignant Transformation ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Rna Expression ◽

Malignant Meningioma ◽

Who Grade ◽

Significant Difference ◽

Who Grade Iii ◽

Grade Iii

Abstract Background Malignant meningiomas comprise 2–5% of all meningiomas. The process of malignant transformation when benign meningiomas (WHO grade I-II) become malignant (WHO grade III) has not previously been investigated in sequential tumour surgeries. Upregulation of FOXM1 expression and DREAM-complex repression have shown phenotypical subgroups correlating with WHO grade and aggressiveness. We investigated the RNA expression of 30 genes central to meningioma biology and 770 genes involved in neuroinflammatory pathways in primary and secondary malignant meningioma patients who underwent one to several operations. Methods We identified a cohort of consecutive malignant meningioma patients treated at Rigshospitalet, Copenhagen from 2000–2020 (n=51) and gathered their malignant tumours and previous WHO grade I/II tumours. The malignant cohort (MC) was counter matched with a benign cohort (BC) where patients had no recurrences during follow-up. RNA expression signatures from 140 samples from the MC and 51 samples from the BC were analysed with the Nanostring Neuroinflammation panel customized with 30 genes known to be relevant in meningioma phenotypes. Results 49% of MC patients had a previous grade I/II meningioma making them secondary malignant meningioma patients. Progression-free survival calculated from first malignant surgery to first recurrence or death showed no significant difference in the primary vs. secondary patients. Preliminary results of single-gene analysis of MC tumours showed FOXM1, MYBL2, TOP2A, BIRC5 expression was higher in WHO grade III samples. Gene-expression signatures in the individual patients and gene ontology enrichment analyses are in process. Conclusions FOXM1, MYBL2, TOP2A, BIRC5 RNA expression levels seem to rise during malignant progression across patients. Gene-expression analysis using the Nanostring technology is feasible and a potentially powerful tool to distinguish meningiomas prone to malignant transformation from truly benign meningiomas.

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189 EFFECT OF THE OVARIAN STIMULATION OF ANESTROUS CATS WITH eCG ON MORPHOLOGICAL QUALITY AND GENE EXPRESSION PROFILE OF CUMULUS-OOCYTE COMPLEXES

Reproduction Fertility and Development ◽

10.1071/rdv29n1ab189 ◽

2017 ◽

Vol 29 (1) ◽

pp. 203 ◽

Cited By ~ 1

Author(s):

D. Veraguas ◽

S. R. Cuevas ◽

P. F. Gallegos ◽

F. O. Castro ◽

L. Rodriguez-Alvarez

Keyword(s):

Gene Expression ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Polar Body ◽

Relative Expression ◽

First Polar Body ◽

Maturation Rate ◽

Grade Ii ◽

Grade Iii

The objective of this research was to evaluate the effect of eCG on morphological quality and gene expression profile of cumulus-oocyte complexes (COC) recovered from anestrous cats. For this purpose, 3 experimental groups were made. Group 1 consisted of 11 oestrous cats (oestrous); Group 2 had 13 anestrous cats (anestrous); and Group 3 was made up of 11 anestrous cats treated with a single subcutaneous dose of 200 IU of eCG. In oestrous and anestrous groups the ovaries were obtained directly by ovariohysterectomy, whereas in the eCG group this was achieved 4 days after the dose injection. In all groups, each cat corresponded to an individual biological replicate, whereby the COC recovered from each cat were classified and processed separately for the experiments of gene expression analysis and in vitro maturation (IVM). The COC were collected by slicing of the ovaries and classified morphologically as grade I (excellent), grade II (good), grade III (fair), and grade IV (poor) quality. For gene expression analysis, pools of 8 to 10 grade I and II immature COC were made, resulting in 7 pools for each group. Quantitative RT-PCR was performed for gonadotrophin receptor genes (FSHR and LHCGR), FSH-induced genes (EGFR, EGR1, ESR2, and PTGS2), and genes related to oocyte competence (GDF9, BMP15, and GATM). The gene SDHA was used as the internal control. The total remaining proportion of grade I and II COC were used for IVM, and maturation rate was measured by visualisation of the first polar body. Statistical analysis was performed using the Kruskal–Wallis test. No differences were found in the total number of COC (mean ± standard deviation) recovered per cat among the oestrous (56.8 ± 20.5), anestrous (80.2 ± 35.2), and eCG groups (96.5 ± 62.0; P > 0.05). With respect to morphological quality of COC, the eCG group had a higher proportion of grade I COC (33.6 ± 11.0%) than the oestrous and anestrous groups (16.5 ± 8.7 and 8.9 ± 6.0%, respectively; P < 0.05). However, the anestrous group had a higher proportion of grade II COC (26.8 ± 6.4%) than the eCG group (21.1 ± 6.6%; P < 0.05). On the other hand, the eCG group had a lower proportion of grade III and IV COC (45.3 ± 12.8%) than the anestrous group (64.3 ± 9.1%; P < 0.05), without differences from the oestrous group (57.1 ± 12.0%; P > 0.05). Concerning to gene expression analysis, COC from the eCG group had a higher relative expression of FSHR, LHCGR, and EGFR than COC from the oestrous and anestrous group (P < 0.05). Furthermore, the COC from the eCG group had a higher relative expression of EGR1 than COC from the anestrous group and a higher expression of ESR2 than COC from the oestrous group (P < 0.05). However, COC from the eCG group had a lower relative expression of GATM and PTGS2 than COC from the oestrous group and a lower expression of GDF9 and BMP15 than COC from the anestrous group (P < 0.05). Although a higher number of oocytes with a first polar body could be seen in the eCG group after IVM, no significant differences in the maturation rate were found among the eCG (55.3 ± 13.2), oestrous (43.7 ± 11.1), and anestrous groups (47.9 ± 13.6; P > 0.05). In conclusion, the treatment with eCG improved the morphological quality of COC recovered from anestrous cats, which agrees with an increased relative expression of FSHR, LHCGR, EGFR, EGR1, and ESR2 and might be related to an enhanced competence of COC.

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Use of gene expression analysis of periampullary carcinomas to identify biliary-like and intestinal-like subgroups of ampullary and duodenal carcinomas.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.161 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 161-161

Author(s):

M. J. Overman ◽

J. Zhang ◽

G. R. Varadhachary ◽

R. F. Hwang ◽

M. Kapoor ◽

...

Keyword(s):

Gene Expression ◽

Hierarchical Clustering ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Kras Mutations ◽

Histologic Subtype ◽

Therapeutic Implications ◽

Periampullary Carcinomas

161 Background: Though adenocarcinomas of the ampulla of Vater are classified as biliary cancers, the epithelium of origin and treatment approach for these rare tumors remains controversial. We compared the gene expression profiles of ampullary carcinomas with that of known periampullary carcinomas. Methods: We analyzed 32 fresh-frozen resected untreated periampullary carcinomas (8 pancreatic, 2 extrahepatic biliary, 8 non-ampullary duodenal, and 14 ampullary) with verified histology and >70% tumor tissue using the Affymetrix U133 Plus 2.0 genome array. Hierarchical clustering of all samples based upon pancreatic and duodenal differentially expressed genes and unsupervised hierarchical clustering was done. Ampullary and duodenal samples were analyzed for histologic subtype (pancreaticobiliary, intestinal, mixed), MSI by PCR, CDX-2 by IHC and KRAS and PI3K mutations by mass spectroscopy-based sequencing (Sequenom). Results: We identified 3 subgroups: pancreatic (8 pancreatic, 1 duodenal), biliary-like (4 duodenal, 7 ampullary, 2 biliary) and intestinal-like (3 duodenal, 7 ampullary). The intestinal-like subgroup had a significantly improved RFS (p=0.03) and OS (p =0.04) compared to the biliary-like subgroup, after stratification by grade and stage. Unsupervised clustering of only ampullary and duodenal samples identified very similar good prognostic (4 duodenal, 5 ampullary) and bad prognostic groups (3 duodenal, 9 ampullary) with 3-year RFS 75% vs. 31%, p =0.05 and 3-year OS 100% vs. 27%, p =0.01. These 2 groups showed no statistically significant differences in adenoma (56% vs 25%), poor differentiation (11% vs 42%), T4 (33% vs 25%), N1 (67% vs 100%), MSI-high (22% vs 0%), KRAS mutations (33% vs 17%), or PI3K mutations (0% vs 17%). CDX-2 expression (100% vs 50%, p=.04) and intestinal histologic subtype (100% vs 0%, p <0.01) were more common in the good prognostic group. Conclusions: Gene expression analysis classifies ampullary carcinomas with duodenal carcinomas and identifies a good prognosis intestinal-like group and a poor prognosis biliary-like group. These findings have therapeutic implications. [Table: see text]

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