Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-Classification and Reveals New Outcome Predictions
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PROVIDER: PRJNA597772 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we report the first examination of Medulloblastoma (MB) methylation patterns in Arab world, using an extensive primary tumor cohort in tertiray care center. We assessed DNA methylation patterns to sub-classify clinical MB cases and their amenability to clinical applications from archival biopsy material (FPPE). We herein establish methylation events as clinically useful biomarkers and demonstrate how their incorporation into current risk-stratification schemes could significantly improve the accuracy of survival predictions in clinical setting. This holds potential for future precision therapeutic approaches aimed at improving the outcomes of afflicted MB patients.
2019-12-27 | GSE142627 | GEO
Project description:Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we show that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.
| S-EPMC7100767 | biostudies-literature
Project description:Ependymoma subpopulation lineages underlie clinical classification and outcome
| PRJNA518917 | ENA
Project description:Refractory/relapsed diffuse large B-cell lymphoma (DLBCL) has a poor prognosis. Novel drugs targeting the constitutively activated NF- B pathway characteristic of ABC-DLBCL are promising, but evaluation depends on accurate activated B cell-like (ABC)/germinal center B cell-like (GCB) molecular classification. This is traditionally performed on gene microarray expression profiles of fresh biopsies, which are not routinely collected, or by immunohistochemistry on formalin-fixed, paraffin-embedded (FFPE) tissue, which lacks reproducibility and classification accuracy. We explored the possibility of using routine archival FFPE tissue for gene microarray applications. We examined Affymetrix HG U133 Plus 2.0 gene expression profiles from paired archival FFPE and fresh-frozen tissues of 40 ABC/GCB-classified DLBCL cases to compare classification accuracy and test the potential for this approach to aid the discovery of therapeutic targets and disease classifiers in DLBCL. Unsupervised hierarchical clustering of unselected present probe sets distinguished ABC/GCB in FFPE with remarkable accuracy, and a Bayesian classifier correctly assigned 32 of 36 cases with >90% probability. Enrichment for NF- B genes was appropriately seen in ABC-DLBCL FFPE tissues. The top discriminatory genes expressed in FFPE separated cases with high statistical significance and contained novel biology with potential therapeutic insights, warranting further investigation. These results support a growing understanding that archival FFPE tissues can be used in microarray experiments aimed at molecular classification, prognostic biomarker discovery, and molecular exploration of rare diseases.
2014-12-29 | GSE64555 | GEO
Project description:Introduction: single-cell RNA sequencing identified multiple subpopulations in childhood posterior fossa ependymoma. The contribution of individual neoplastic subpopulations to bulk tumor transcriptome-based molecular classification and patient outcome was estimated by deconvolution in a cohort of clinically-annotated primary and recurrent EPN samples. The abundance of EPN subpopulations was estimated in primary EPN samples and showed that the ratio of subpopulation fractions dictated assignment to the two main transcriptomic classification subgroups in childhood posterior fossa ependymoma. Longitudinal analysis revealed that subpopulation fractions changed between presentation and recurrence. Outcome analyses demonstrated that a different proportions of subpopulations were associated with differential survival.
2020-07-31 | GSE125861 | GEO
Project description:New Targeted Approaches for Epigenetic Age Predictions
| PRJNA636753 | ENA
Project description:Ependymoma (EPN) is a brain tumor commonly presenting in childhood that remains fatal in the majority of children. Intra-tumoral cellular heterogeneity in bulk tumor samples significantly confounds our understanding of EPN biology, impeding development of effective therapy. We used single-cell RNA sequencing to identify four neoplastic cell subpopulations in posterior fossa EPN patient samples that underlie traditional subgroup classification and harbor divergent lineage trajectories and clinical outcomes. Neoplastic subpopulations expressed gene signatures associated with normal ependyma, ependymoma, and mesenchymal phenotypes, consequently named ciliated (CEC), transportive (TEC), undifferentiated (UEC), and mesenchymal ependymoma cells (MEC). The abundance of EPN subpopulations as estimated by deconvolution of EPN bulk tumor transcriptomes showed that the ratio of MEC and CEC cell fractions dictated assignment to the two main classification subgroups in PFA. Longitudinal analysis revealed evolution of subpopulation fractions, notably MEC and CEC, which changed between presentation and recurrence. Outcome analyses demonstrated that a higher proportion of UEC or MEC subpopulations was associated with shorter survival, whereas CEC was associated with longer survival. Unsupervised pseudotime analysis revealed divergent subpopulation lineages. The first lineage conformed to a classic cancer stem cell trajectory where UEC progenitors differentiate sequentially to TECs and then CECs. In the second trajectory MECs arise from UECs via TECs, potentially in response to hypoxia-mediated cellular stress, a process that we recreated in vitro in a hypoxia treated EPN cell line. Our study reveals the existence of significant, unappreciated cellular heterogeneity in EPN and provides important resolution of EPN tumor biology.
2020-07-31 | GSE125969 | GEO
Project description:Accurate diagnostic discrimination of benign renal oncocytoma (OC) and malignant renal cell carcinomas (RCC) is not only useful for planning appropriate treatment strategies of patients with renal masses but also for estimating prognosis. Classification of renal neoplasms solely by histopathology can often be challenging for a variety of reasons. The aim of this study was to develop and validate a genomic algorithm for molecular classification of renal cortical neoplasms that could be implemented in a routine clinical diagnostic setting. Using TCGA (The Cancer Genome Atlas) copy number profiles of over 600 RCC specimens, prior FISH studies and published literature, a classification algorithm was developed consisting of 15 genomic markers: loss of VHL, 3p21, 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q, 20q, and chromosomes 3, 7, and 12. Criteria for scoring specimens for the presence of each genomic marker were established. As validation, 191 surgically resected formalin-fixed paraffin-embedded renal neoplasms were blindly submitted to targeted array-CGH and were classified according to the algorithm. Upon histologic re-review leading to exclusion of three specimens and using histology as the gold standard, the algorithm correctly classified 58 of 62 (93%) clear cell renal cell carcinoma, 51 of 56 (91%) papillary RCC, and 33 of 34 (97%) chromophobe RCC. Of the 36 OC specimens, 17 were classified as OC, two as a malignant subtype, 14 as benign, and three exhibited alterations not associated with a specific subtype. In ten of the latter two groups, CCND1-rearrangement was detected by fluorescence in situ hybridization, affording a classification as OC. Together, 33 of 36 (92%) OC were classified as OC or benign. For the entire validation cohort, an overall diagnostic sensitivity of 93% and above 97% specificity was achieved, suggesting that the implementation of genome-based molecular classification in a clinical diagnostic setting could impact the overall management and outcome of patients with renal tumors. A total of 191 RCC FFPE samples are analyzed including 63 clear cell RCC (ccRCC), 57 papillary RCC (pRCC), 35 chromophobe RCC (chrRCC) and 36 oncocytoma (OC). Two-color array-comparative genomic hybdrization on custom designed using RCC DNA as test and normal sex-matched DNA as reference.
2015-04-29 | E-GEOD-57162 | biostudies-arrayexpress
Project description:Ependymoma subpopulation lineages underlie clinical classification and outcome (microarray data set)
| PRJNA517721 | ENA
Project description:Ependymoma subpopulation lineages underlie clinical classification and outcome (scRNAseq data set)
| PRJNA518131 | ENA