Abstract:The Group 3 Medulloblastoma ( Grp3-MB ) is an aggressive molecular subtype with a high incidence of metastasis and deaths. In this study, were used an RNA sequencing data ( RNA-Seq ) from a Brazinian cohort of MBs to identify hub genes associated with the metastatic risk. Data validation were performed by using multiple large datasets from MBs (GSE85217, GSE37418, EGAS00001001953). DESeq2 package in R software was used to identify the differentially expressed genes ( DEGs ) in our RNA-Seq data. The DEGs data w… Show more
“…A high level of KIRREL2 expression was also associated with unfavorable survival for all second-generation subgroups from II to VII (not shown). However, we did not find any clinical significance for genes which were previously reported as molecular Grp 3 MB prognosticators [ 2 , 8 , 9 , 18 , 19 , 24 , 27 , 33 ] but were not included in the current DEG set (Online Resource Supplementary Table 2). Fig.…”
Section: Resultsmentioning
confidence: 62%
“…Therefore, a more refined understanding of Grp 3 MB molecular heterogeneity is urgently needed for improved risk stratification, optimization of current treatments, and the development of subgroup-directed therapies. Studies investigating the clinical significance of various molecular features in Grp 3 MB at higher genomic resolution have recently been reported, identifying a wide range of prognostically relevant molecular patterns and subtypes [ 2 , 3 , 8 , 9 , 11 , 15 , 18 – 21 , 24 , 27 – 30 ]. Thus, combined multiple class-definition approaches to DNA-methylation profiles of Grp 3/Grp 4 MB identified eight second-generation subgroups, labeled I–VIII [ 21 , 29 ].…”
Medulloblastomas (MB) molecularly designated as Group 3 (Grp 3) MB represent a more clinically aggressive tumor variant which, as a group, displays heterogeneous molecular characteristics and disease outcomes. Reliable risk stratification of Grp 3 MB would allow for appropriate assignment of patients to aggressive treatment protocols and, vice versa, for sparing adverse effects of high-dose radio-chemotherapy in patients with standard or low-risk tumors. Here we performed RNA-based analysis on an international cohort of 179 molecularly designated Grp 3 MB treated with HIT protocols. We analyzed the clinical significance of differentially expressed genes, thereby developing optimal prognostic subdivision of this MB molecular group. We compared the transcriptome profiles of two Grp 3 MB subsets with various outcomes (76 died within the first 60 months vs. 103 survived this period) and identified 224 differentially expressed genes (DEG) between these two clinical groups (Limma R algorithm, adjusted p-value < 0.05). We selected the top six DEG overexpressed in the unfavorable cohort for further survival analysis and found that expression of all six genes strongly correlated with poor outcomes. However, only high expression of KIRREL2 was identified as an independent molecular prognostic indicator of poor patients’ survival. Based on clinical and molecular patterns, four risk categories were outlined for Grp 3 MB patients: i. low-risk: M0-1/MYC non-amplified/KIRREL2 low (n = 48; 5-year OS—95%); ii. standard-risk: M0-1/MYC non-amplified/KIRREL2 high or M2-3/MYC non-amplified/KIRREL2 low (n = 65; 5-year OS—70%); iii. high-risk: M2-3/MYC non-amplified/KIRREL2 high (n = 36; 5-year OS—30%); iv. very high risk—all MYC amplified tumors (n = 30; 5-year OS—0%). Cross-validated survival models incorporating KIRREL2 expression with clinical features allowed for the reclassification of up to 50% of Grp 3 MB patients into a more appropriate risk category. Finally, KIRREL2 immunopositivity was also identified as a predictive indicator of Grp 3 MB poor survival, thus suggesting its application as a possible prognostic marker in routine clinical settings. Our results indicate that integration of KIRREL2 expression in risk stratification models may improve Grp 3 MB outcome prediction. Therefore, simple gene and/or protein expression analyses for this molecular marker could be easily adopted for Grp 3 MB prognostication and may help in assigning patients to optimal therapeutic approaches in prospective clinical trials.
“…A high level of KIRREL2 expression was also associated with unfavorable survival for all second-generation subgroups from II to VII (not shown). However, we did not find any clinical significance for genes which were previously reported as molecular Grp 3 MB prognosticators [ 2 , 8 , 9 , 18 , 19 , 24 , 27 , 33 ] but were not included in the current DEG set (Online Resource Supplementary Table 2). Fig.…”
Section: Resultsmentioning
confidence: 62%
“…Therefore, a more refined understanding of Grp 3 MB molecular heterogeneity is urgently needed for improved risk stratification, optimization of current treatments, and the development of subgroup-directed therapies. Studies investigating the clinical significance of various molecular features in Grp 3 MB at higher genomic resolution have recently been reported, identifying a wide range of prognostically relevant molecular patterns and subtypes [ 2 , 3 , 8 , 9 , 11 , 15 , 18 – 21 , 24 , 27 – 30 ]. Thus, combined multiple class-definition approaches to DNA-methylation profiles of Grp 3/Grp 4 MB identified eight second-generation subgroups, labeled I–VIII [ 21 , 29 ].…”
Medulloblastomas (MB) molecularly designated as Group 3 (Grp 3) MB represent a more clinically aggressive tumor variant which, as a group, displays heterogeneous molecular characteristics and disease outcomes. Reliable risk stratification of Grp 3 MB would allow for appropriate assignment of patients to aggressive treatment protocols and, vice versa, for sparing adverse effects of high-dose radio-chemotherapy in patients with standard or low-risk tumors. Here we performed RNA-based analysis on an international cohort of 179 molecularly designated Grp 3 MB treated with HIT protocols. We analyzed the clinical significance of differentially expressed genes, thereby developing optimal prognostic subdivision of this MB molecular group. We compared the transcriptome profiles of two Grp 3 MB subsets with various outcomes (76 died within the first 60 months vs. 103 survived this period) and identified 224 differentially expressed genes (DEG) between these two clinical groups (Limma R algorithm, adjusted p-value < 0.05). We selected the top six DEG overexpressed in the unfavorable cohort for further survival analysis and found that expression of all six genes strongly correlated with poor outcomes. However, only high expression of KIRREL2 was identified as an independent molecular prognostic indicator of poor patients’ survival. Based on clinical and molecular patterns, four risk categories were outlined for Grp 3 MB patients: i. low-risk: M0-1/MYC non-amplified/KIRREL2 low (n = 48; 5-year OS—95%); ii. standard-risk: M0-1/MYC non-amplified/KIRREL2 high or M2-3/MYC non-amplified/KIRREL2 low (n = 65; 5-year OS—70%); iii. high-risk: M2-3/MYC non-amplified/KIRREL2 high (n = 36; 5-year OS—30%); iv. very high risk—all MYC amplified tumors (n = 30; 5-year OS—0%). Cross-validated survival models incorporating KIRREL2 expression with clinical features allowed for the reclassification of up to 50% of Grp 3 MB patients into a more appropriate risk category. Finally, KIRREL2 immunopositivity was also identified as a predictive indicator of Grp 3 MB poor survival, thus suggesting its application as a possible prognostic marker in routine clinical settings. Our results indicate that integration of KIRREL2 expression in risk stratification models may improve Grp 3 MB outcome prediction. Therefore, simple gene and/or protein expression analyses for this molecular marker could be easily adopted for Grp 3 MB prognostication and may help in assigning patients to optimal therapeutic approaches in prospective clinical trials.
“…RALGPS1 and RALGPS2 contain pleckstrin homology domains but their means of regulation are not well understood [47]. In cancer, elevated expression of numerous RALGEFs is associated with poor survival and increased local invasion and distant metastasis [48][49][50][51][52]. Downregulation of several RALGEFs has been shown to decrease the invasion and migration of cancer cells both in vitro and in vivo through decreased RALA or RALB activity [49,[52][53][54][55][56][57][58].…”
RALA and RALB are highly homologous small G proteins belonging to the RAS superfamily. Like other small GTPases, the RALs are molecular switches that can be toggled between inactive GDP-bound and active GTP-bound states to regulate diverse and critical cellular functions such as vesicle trafficking, filopodia formation, mitochondrial fission, and cytokinesis. The RAL paralogs are activated and inactivated by a shared set of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) and utilize similar sets of downstream effectors. In addition to their important roles in normal cell biology, the RALs are known to be critical mediators of cancer cell survival, invasion, migration, and metastasis. However, despite their substantial similarities, the RALs often display striking functional disparities in cancer. RALA and RALB can have redundant, unique, or even antagonistic functions depending on cancer type. The molecular basis for these discrepancies remains an important unanswered question in the field of cancer biology. In this review we examine the functions of the RAL paralogs in normal cellular physiology and cancer biology with special consideration provided to situations where the roles of RALA and RALB are non-redundant.
“…For example, the lower expression of ITRR1 and its coregulated genes ( ATP1A2, MTTL7A, RGL1 ) are associated with processes in MB, and the lower expression of ANTXR1 and RGL1 are significantly correlated with worse overall survival (OS). [ 10 ] However, until now fewer clinical studies have identified novel genes directly against metastasis of MB. Accordingly, further investigation of metastasis related genes is helpful to better understand the molecular mechanisms of the occurrence of MB metastasis and provide more options for clinical treatment.…”
Medulloblastoma (MB) is one of the most frequent malignant brain tumors in children. The metastasis of MB outside the nervous system is associated with a poor prognosis. Our study aimed to explore the genes correlated with metastasis in MB. Using the data downloaded from the gene expression omnibus database, the differentially expressed genes were identified between the metastatic and nonmetastatic samples in MB, which were undergone functional enrichment. Prognosis related genes were identified using univariate Cox regression analysis. The gene set enrichment analysis was conducted to find MB metastasis related pathways. A total of 196 differentially expressed genes were identified between metastatic and nonmetastatic samples in MB patients, and these genes were significantly enriched in 483 gene ontology terms and 29 Kyoto encyclopedia of genes and genomes pathways. In addition, univariate Cox regression analysis screened the top 10 genes (
CEMIP, GLCE, ART3, GABRA5, COLEC12, LIN28B, ZNF521, IL17RB, Fas apoptotic inhibitory molecule 2 (FAIM2
),
RCBTB2
) that were significantly associated with survival of MB, among which
FAIM2
was prominently expressed in cerebral cortex, cerebellum and hippocampus. The expression of
FAIM2
was decreased in metastatic MB samples, and
FAIM2
harbored missense mutations, amplifications and deep deletions in metastatic samples of MB. Moreover, a total of 25 pathways were significantly activated and 41 pathways were significantly inhibited in
FAIM2
high expression group compared to
FAIM2
low expression group in MB patients.
FAIM2
was tightly correlated with metastasis in MB patients, and the low expression of
FAIM2
was associated with poor prognosis.
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