Gene expression analysis of relapse and no-relapse Wilms tumor
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22696 | GEO | 2011/06/01
SECONDARY ACCESSION(S): PRJNA128307
REPOSITORIES: GEO
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Project description:Wilms tumor (WT), the commonest renal tumor of the childhood, is originated from pluripotent metanephric blastemal cells resulting in tumors with triphasic histology, composed by blastemal, epithelial, and stromal cells. Histological subtype and tumor stage have long been recognized as important prognostic factors and used for the current therapeutic approach with blastema considered as the component with the highest clinical impact. Current clinical and molecular research is directed toward identifying prognostic factors for both purposes, definition of the minimal or intense required therapy for successful treatment of children with low or high risk of relapse, respectively. In this study, to identify molecular prognostic markers predictive of tumor relapse, samples from 26 advanced (Stage III or IV) blastemal WT, whose patients presented (13 samples) or did not present (13 samples) relapse, were interrogated by 4,608 human genes immobilized in a customized cDNA platform. This analysis revealed a set of 69 differentially expressed genes, where the nine top genes were evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were technically confirmed showing down-regulation in relapse WT. TSPAN3 and NCOA6 were validated in an independent sample group. Gene trios containing these two genes combined with one of the remaining three reported a reasonable capability of discriminating relapse and no-relapse WT. Negative protein expression of MCM2 and NCOA6 was observed in around 62% and 72% of 34 independent stage III and IV WT patients, respectively without association with relapse. However, a significant association between MCM2 negative staining and chemotherapy as first treatment was observed suggesting that MCM2 protein expression is implicated anyhow with chemotherapy treatment in WT. Twenty-six blastemal-enriched advanced stage (III or IV) WT samples from sporadic and favorable histology WT were received from Children Oncology Group (COG) and used were used for microarray experiments, from which 13 samples were from patients without relapse in 5 years of follow up. Tumors were taken from primary nephrectomy at the time of initial diagnosis. Blastemal histological component was isolated following protocol described in Maschietto et al. (2008). Only samples with >80% of blastemal cells were used. Total RNA was isolated using TRIzol (Sigma) according to manufacturer´s instructions. RNA quantity and integrity was assessed by spectrophotometry (Nanodrop) and microfluidics-based electrophoresis (Agilent 2100 Bioanalyzer, Agilent), respectively, selecting only RNA samples with OD around 2.0 and RIN>5.0. A two-round RNA amplification procedure (Gomes et al. 2003) was carried out for all samples. Labeled cDNA was generated in a reverse transcriptase reaction using 4 ug of amplified RNA (aRNA), random hexamer primer (Invitrogen Life Technologies, Carlsbad, CA), Alexa-3 or 5-labeled dCTP (Amersham, Biosciences) and IMPROM (PROMEGA) using oligo-dT7(24), following manufacture recommendations. Five µg of test and reference cDNA reverse color Alexa-labeled aRNA targets were competitively hybridized against the cDNA probes in a customized cDNA platform with 4,608 ORESTES representing human genes. Dye-swap was performed for each sample as control for dye bias and used as replicate. Pre-hybridization and hybridization were performed as described (Maschietto et al. 2008). A pool of RNAs obtained from 15 distinct human cell lines as was used as reference. Signal intensities capture and analysis were performed as described in Maschietto et al (2008).
2011-06-01 | E-GEOD-22696 | biostudies-arrayexpress
Project description:Wilms' tumor (WT) is the most common pediatric kidney cancer with more than a 90% overall survival rate in response to standard chemotherapy. However, less-differentiated blastemal type of WT often metastasize and relapse. To remodel the high-risk WT for therapeutic intervention, we partially reprogrammed WIT49, a mixed type of WT cell line, to iPSCs, which we termed as WiT49-PRCs (Partial reprogrammed iPSCs). WiT49-PRCs express stem cell markers. When implanted into the kidney capsule in mice, WiT49-PRCs formed kidney tumors and developed both liver and lung metastases, whereas WiT49 tumors do not metastasize. Histological characterization and gene expression signatures demonstrated that WiT49-PRC recapitulates blastema-dominant WTs. Moreover, screening FDA-approved drugs in isogeneic WiT49 and WiT49-PRC cells led to the identification of epithelial- or blastemal-dominant WT-sensitive drugs. A subset of drugs was discovered with selectivity towards blastemal WT patient derived xenografts (PDXs). HDAC inhibitors (e.g. panobinostat and romedipsin) were found universally effective across different WT and more potent than doxorubicin in PDXs. Taken together, WiT49-PRC serves as a blastemal-dominant WT model for therapeutic intervention to improve the treatment of high-risk WT patients.
2024-11-06 | GSE246479 | GEO
Project description:Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse. Using ERRBS, we profiled genome-wide DNA methylation patterns of non-relapse DLBCL tumor samples at diagnosis, relaspe DLBCL patient samples at diagnosis and relaspe.
2015-04-14 | E-GEOD-66329 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of relapse and relapse-free T-cell lymphoblastic lymphoma (T-LBL) samples. The Illumina 850k Human DNA methylation EPIC BeadChip was used to obtain DNA methylation profiles across approximately 850,000 CpGs in T-LBL samples. Samples included 21 relapse T-LBL samples, and 28 relapse-free T-LBL samples.
2020-05-04 | GSE131677 | GEO
Project description:Here we characterize an association between disease progression and DNA methylation in Diffuse Large B cell Lymphoma (DLBCL). By profiling genome-wide DNA methylation at single base-pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show DLBCL patients exhibit heterogeneous evolution of tumor methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse–associated methylation signature converging on key pathways such as transforming growth factor beta (TGF-beta) receptor activity. We also observe decreased intra-tumor methylation heterogeneity from diagnosis to relapsed tumor samples. Relapse-free patients display lower intra-tumor methylation heterogeneity at diagnosis compared to relapsed patients in an independent validation cohort. Furthermore, intra-tumor methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.
2015-04-14 | GSE66329 | GEO
Project description:Purpose: Our study aimed to disclose the specific gene expression profile representing peritoneal relapses inherent in primary gastric cancers and to identify patients at high risk of peritoneal relapse in a prospective study on the basis of the molecular prediction. Experimental Design: RNA samples from 141 primary gastric cancer tissues after curative surgery were profiled using oligonucleotide microarrays covering 30,000 human probes. Firstly we constructed molecular prediction system and validated the robustness and prognostic validity of the analysis by 500 times multiple random sampling in 56 retrospective set consisting of 38 relapse free and 18 peritoneal relapse patients. Secondly we applied this prediction to 85 prospective set to assess the predictive accuracy and prognostic validity. Results: In retrospective phase, 500 times multiple random sampling analysis yielded 68% predictive accuracy in average and 22 gene expression profile associated with peritoneal relapse was identified. This prediction could identify significantly poor prognostic patients. In prospective phase, the molecular prediction yielded 76.9% overall accuracy. KaplanâMeier analysis with peritoneal relapse free survival showed a significant difference between âgood signature groupâ and âpoor signature groupâ (Log-rank p=0.0017). Multivariate analysis by Cox regression hazards model revealed that the molecular prediction was the only independent peritoneal relapse prognostic factor. Conclusions: Gene expression profile inherent in primary gastric cancer tissues can be useful to predict peritoneal relapse prospectively after curative surgery and individualize postoperative management to improve the prognosis of advanced gastric cancers. Of 141 samples, 56 represented the retrospective phase and 85 represented the prospective phase.
2010-05-23 | E-GEOD-15081 | biostudies-arrayexpress
Project description:Early cutaneous squamous cell carcinomas (cSCCs) show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits and are associated with tumor relapse, metastasis, and poor survival. Prognostic biomarkers for cSCC relapse must therefore be found that accurately predict the clinical course of the disease, since established markers are suboptimal. Using mouse models of cSCC progression, we showed that the emergence of epithelial plastic cancer cells with a hybrid epithelial/mesenchymal phenotype promotes tumor progression to a mesenchymal state. These cells can be identified early on by the expression of integrin αV (ITGAV). Analysis of ITGAV expression in a cohort of primary cSCCs from patients provided prognostic information about the risk of relapse beyond current histopathological parameters. Together, our findings provide an opportunity to clinically implement ITGAV by standard immunodetection approaches and thereby improve patient stratification and therapeutic management.
2024-08-08 | GSE233382 | GEO
Project description:Purpose: Our study aimed to disclose the specific gene expression profile representing peritoneal relapses inherent in primary gastric cancers and to identify patients at high risk of peritoneal relapse in a prospective study on the basis of the molecular prediction. Experimental Design: RNA samples from 141 primary gastric cancer tissues after curative surgery were profiled using oligonucleotide microarrays covering 30,000 human probes. Firstly we constructed molecular prediction system and validated the robustness and prognostic validity of the analysis by 500 times multiple random sampling in 56 retrospective set consisting of 38 relapse free and 18 peritoneal relapse patients. Secondly we applied this prediction to 85 prospective set to assess the predictive accuracy and prognostic validity. Results: In retrospective phase, 500 times multiple random sampling analysis yielded 68% predictive accuracy in average and 22 gene expression profile associated with peritoneal relapse was identified. This prediction could identify significantly poor prognostic patients. In prospective phase, the molecular prediction yielded 76.9% overall accuracy. Kaplan–Meier analysis with peritoneal relapse free survival showed a significant difference between ‘good signature group’ and ‘poor signature group’ (Log-rank p=0.0017). Multivariate analysis by Cox regression hazards model revealed that the molecular prediction was the only independent peritoneal relapse prognostic factor. Conclusions: Gene expression profile inherent in primary gastric cancer tissues can be useful to predict peritoneal relapse prospectively after curative surgery and individualize postoperative management to improve the prognosis of advanced gastric cancers.
2009-03-04 | GSE15081 | GEO
Project description:Background: Since the high relapse rate is considered to be responsible for the poor survival of stage M neuroblastoma patients, we tested whether the genomic information of bone marrow-derived disseminated tumor cells (DTCs) would help to better understand tumor evolution and to characterize the relapse-seeding clone. Methods: Seven samples from different regions of a primary tumor of a stage M neuroblastoma patient, corresponding DTCs at diagnosis, and DTCs and a metastatic tumor at relapse were analyzed by a high-density SNP array. Relapse-associated chromosomal aberrations found in this case were then validated in DTCs and tumor samples of 154 stage M neuroblastoma patients. Findings: In this case study, unique aberrations were evident in certain tissue/time points aside from a high concordance of genomic aberrations between all analyzed samples. Surprisingly, DTCs at diagnosis, and DTCs and the metastatic tumor at relapse all displayed a terminal deletion in 1q which was not detected in any of the primary tumor samples. In the validation cohort, 1q terminal deletions were found with a higher frequency in DTCs at diagnosis (17.8%) and at relapse (27.5%) compared to primary tumors (11%). 1q deletions were significantly associated with 19q and ATRX deletions. The presence of each individual aberration in the diagnostic DTCs was associated with an increased likelihood of an adverse event and in case of 19q deletion with a decreased overall survival. Moreover, PTPRD deletion and loss of chromosome Y had significantly higher frequencies in the relapse samples compared to the diagnostic samples. Interpretation: These data strongly suggest a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. In addition, the higher frequency of relapse-associated genomic aberrations in the diagnostic DTCs compared to the primary tumors and their effect on the event-free survival rate indicate that analysis of DTCs at diagnosis may provide a higher probability for detecting the relapse-seeding clone compared to the primary tumor. Background: Since the high relapse rate is considered to be responsible for the poor survival of stage M neuroblastoma patients, we tested whether the genomic information of bone marrow-derived disseminated tumor cells (DTCs) would help to better understand tumor evolution and to characterize the relapse-seeding clone. Methods: Seven samples from different regions of a primary tumor of a stage M neuroblastoma patient, corresponding DTCs at diagnosis, and DTCs and a metastatic tumor at relapse were analyzed by a high-density SNP array. Relapse-associated chromosomal aberrations found in this case were then validated in DTCs and tumor samples of 154 stage M neuroblastoma patients. Findings: In this case study, unique aberrations were evident in certain tissue/time points aside from a high concordance of genomic aberrations between all analyzed samples. Surprisingly, DTCs at diagnosis, and DTCs and the metastatic tumor at relapse all displayed a terminal deletion in 1q which was not detected in any of the primary tumor samples. In the validation cohort, 1q terminal deletions were found with a higher frequency in DTCs at diagnosis (17.8%) and at relapse (27.5%) compared to primary tumors (11%). 1q deletions were significantly associated with 19q and ATRX deletions. The presence of each individual aberration in the diagnostic DTCs was associated with an increased likelihood of an adverse event and in case of 19q deletion with a decreased overall survival. Moreover, PTPRD deletion and loss of chromosome Y had significantly higher frequencies in the relapse samples compared to the diagnostic samples. Interpretation: These data strongly suggest a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. In addition, the higher frequency of relapse-associated genomic aberrations in the diagnostic DTCs compared to the primary tumors and their effect on the event-free survival rate indicate that analysis of DTCs at diagnosis may provide a higher probability for detecting the relapse-seeding clone compared to the primary tumor.
2017-08-31 | GSE84291 | GEO
Project description:Relapse is the most common cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL) and is often difficult to predict. To explore the prognostic impact of recurrent DNA copy number abnormalities on relapse, we performed high-resolution genomic profiling of 34 paired diagnosis-relapse ALL samples. Recurrent lesions detected at diagnosis, including PAX5, CDKN2A, and EBF1, were frequently absent at relapse, indicating that they represent secondary events that may be absent in the relapse-prone therapy-resistant progenitor cell. In contrast, deletions and nonsense mutations in IKZF1 (IKAROS), were highly enriched and consistently preserved at the time of relapse. A targeted copy number screen in an unselected cohort of 131 precursor B-ALL cases, enrolled in the dexamethasone-based Dutch Childhood Oncology Group treatment protocol ALL9, revealed that IKZF1 deletions are significantly associated with poor relapse-free and overall survival rates. Separate analysis of ALL9-treatment subgroups revealed that non-high-risk patients with IKZF1 deletions exhibited a ~12-fold higher relative relapse rate than those without IKZF1 deletions. Consequently, IKZF1 deletion status allowed the prospective identification of 53% of the relapse-prone non-high-risk-classified patients within this subgroup and, therefore, serves as one of the strongest predictors of relapse at the time of diagnosis with high potential for future risk stratification. Affymetrix NspI 250k array data of 34 paired diagnosis and relapse samples of pediatric ALL. From 13 patients a complete remission sample was available. Four cases had 2 relapses.
2010-03-01 | GSE20353 | GEO