Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150402 | GEO | 2021/01/19
REPOSITORIES: GEO
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Project description:MGMT promoter methylation status is currently the only established molecular prognosticator in IDH wild-type glioblastoma multiforme (GBM). Therefore, we aimed to discover novel therapy-associated epigenetic biomarkers. After enrichment for hypermethylated fractions using methyl-CpG-immunoprecipitation (MCIp), we performed global DNA methylation profiling for 14 long-term (LTS; >36 months) and 15 short-term (STS; 6â??10 months) surviving GBM patients. Even after exclusion of the G-CIMP phenotype, we observed marked differences between the LTS and STS methylome. A total of 1,247 probes in 706 genes were hypermethylated in LTS and 463 probes in 305 genes were found to be hypermethylated in STS patients (p values < 0.05, log2 fold change ± 0.5). We identified 13 differentially methylated regions (DMRs) with a minimum of four differentially methylated probes per gene. Indeed, we were able to validate a subset of these DMRs through a second, independent method (MassARRAY) in our LTS/STS training set (ADCY1, GPC3, LOC283731/ISLR2). These DMRs were further assessed for their prognostic capability in an independent validation cohort (n = 62) of non-G-CIMP GBMs from the TCGA. Hypermethylation of multiple CpGs mapping to the promoter region of LOC283731 correlated with improved patient outcome (p < 0.03). The prognostic performance of LOC283731 promoter hypermethylation was confirmed in a third independent study cohort (n = 89), and was independent of gender, performance (KPS) and MGMT status (p < 0.0485, HR = 0.63). Intriguingly, the prediction was most pronounced in younger GBM patients (<60 years). In conclusion, we provide compelling evidence that promoter methylation status of this novel gene is a prognostic biomarker in IDH1 wild-type/non-G-CIMP GBMs. Global DNA methylation profiling in 14 long-term and 15 short-term surviving glioblastoma patients. DNA of 7 normal brain samples were pooled to create a control DNA for two-color analysis.
2016-03-10 | E-GEOD-74561 | biostudies-arrayexpress
Project description:BackgroundDespite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis.ResultsTo address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as 'low risk' by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0-3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score.ConclusionsThis study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0-3).
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Project description:MGMT promoter methylation status is currently the only established molecular prognosticator in IDH wild-type glioblastoma multiforme (GBM). Therefore, we aimed to discover novel therapy-associated epigenetic biomarkers. After enrichment for hypermethylated fractions using methyl-CpG-immunoprecipitation (MCIp), we performed global DNA methylation profiling for 14 long-term (LTS; >36 months) and 15 short-term (STS; 6–10 months) surviving GBM patients. Even after exclusion of the G-CIMP phenotype, we observed marked differences between the LTS and STS methylome. A total of 1,247 probes in 706 genes were hypermethylated in LTS and 463 probes in 305 genes were found to be hypermethylated in STS patients (p values < 0.05, log2 fold change ± 0.5). We identified 13 differentially methylated regions (DMRs) with a minimum of four differentially methylated probes per gene. Indeed, we were able to validate a subset of these DMRs through a second, independent method (MassARRAY) in our LTS/STS training set (ADCY1, GPC3, LOC283731/ISLR2). These DMRs were further assessed for their prognostic capability in an independent validation cohort (n = 62) of non-G-CIMP GBMs from the TCGA. Hypermethylation of multiple CpGs mapping to the promoter region of LOC283731 correlated with improved patient outcome (p < 0.03). The prognostic performance of LOC283731 promoter hypermethylation was confirmed in a third independent study cohort (n = 89), and was independent of gender, performance (KPS) and MGMT status (p < 0.0485, HR = 0.63). Intriguingly, the prediction was most pronounced in younger GBM patients (<60 years). In conclusion, we provide compelling evidence that promoter methylation status of this novel gene is a prognostic biomarker in IDH1 wild-type/non-G-CIMP GBMs.
2016-03-10 | GSE74561 | GEO
Project description:Background: Less than 5% of glioblastoma multiforme (GBM) patients survive more than 5-years (long-term survivors, LTS). Nevertheless, the molecular fingerprint of LTS remains uncharted. We aimed to characterize LTS by clinicopathological assessment, DNA methylation (DNAm)/Copy Number Variation (CNV) and mutation profiling. Methods: This multicentric project proposed by Alliance Against Cancer was coordinated by Fondazione IRCCS Istituto Neurologico Carlo Besta. One-hundred forty-two LTS patients were screened, and samples centrally reviewed; 95 patients were enrolled. DNAm profiles and sequencing were performed on 27 LTS and 24 standard survival GBM (STS). Results: We focused on 73 IDHwt-LTS. All patients underwent at least partial resection, followed by Stupp protocol (48/70). The median time to progression was 43 months (4-186), and almost all received a second treatment. Morphological and routine diagnostic molecular features of LTS did not deviate from the classic findings. MGMT promoter methylation was detected in 92% of cases. No significant differences were observed between LTS and STS in terms of prevalence of mutated genes, with TP53 as the most commonly mutated gene (26% of all samples). DNAm showed a more heterogeneous group for LTS, with several cases classified as pediatric high-grade glioma and peculiar CNVs. We identified 18 differentially methylated regions, 4 associated with survival probability (NR2F2, MME, WDR66 and ENPP4). Methylation levels of individual probes in IGFBP3 gene and corresponding protein expression showed a significant correlation with survival. Conclusions: We found no significant different morphology nor mutational profile of LTS. DNAm confirmed as a valuable tool for GBM classification. No specific episignature was detected, but methylation levels of specific genes had prognostic value in LTS.
2024-03-31 | GSE230770 | GEO
Project description:In this dataset, we included expression data obtained from 30 resected human PDAC tumors, to examine what genes are differentially expressed in different cohorts that might lead to various outcomes The two cohorts we have are defined as short term survivors (STS) with median survival of >3 month and <1 year postsurgery, and long term survivors (LTS) with overall survival of >3 years postsurgery.
2016-11-18 | GSE89997 | GEO
Project description:Purpose: Autologous tumor lysate-pulsed dendritic cell (DC) vaccination has shown promising long-term survival in a cohort of patients with newly diagnosed glioblastoma. The purpose of this study was to better understand the mechanisms and modulation of the immune microenvironment underlying the clinical efficacy of DC-based vaccine therapy. Experimental Design: We performed bulk RNA sequencing on tumor samples from patients with newly diagnosed glioblastoma obtained prior to treatment with dendritic cell vaccination. We characterized the molecular mechanisms and immune microenvironments of long-term survivors (LTS, n= 8), medium-term survivors (MTS, n= 13), and short-term survivors (STS, n = 17). Results: There was an enrichment of the mesenchymal subtype of glioblastoma in the long-term survival group. Additionally, decreased tumor cell density, upregulation of cell surface markers, and increased neuronal activity were associated with the longer survival cohorts. Two microglia populations, one associated with increased survival and one associated with decreased survival in the DC-treated cohorts, but not standard of care (SOC) cohorts, are also potentially implicated in response to DC immunotherapy. There were increases in functional activity of the immune environment in longer survivor cohorts. Conclusions: These analyses suggest the potential to identify tumor-based predictive factors that may be associated with favorable responses to DC vaccination in glioblastoma patients; and if validated, these findings may enable better patient selection for future clinical trials.
2023-12-11 | GSE249282 | GEO
Project description:Proteomics has been little used for the identification of novel prognostic and/or therapeutic markers in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GB). In this study, we analyzed 50 tumor and 30 serum samples from short- and long-term survivors of IDH-wildtype GB (STS and LTS, respectively) by data-independent acquisition mass spectrometry (DIA-MS)-based proteomics, with the aim of identifying such markers. DIA-MS identified 5422 and 826 normalized proteins in tumor and serum samples, respectively, with only three tumor proteins and 26 serum proteins displaying significant differential expression between the STS and LTS groups. These dysregulated proteins were principally associated with the detoxification of reactive oxygen species (ROS). In particular, GB patients in the STS group had high serum levels of malate dehydrogenase 1 (MDH1) and ribonuclease inhibitor 1 (RNH1) and low tumor levels of fatty acid-binding protein 7 (FABP7), which may have enabled them to maintain low ROS levels, counteracting the effects of the first-line treament with radiotherapy plus concomitant and adjuvant temozolomide. A blood score built on the levels of MDH1 and RNH1 expression was found to be an independent prognostic factor for survival based on the serum proteome data for a cohort of 96 IDH-wildtype GB patients. This study highlights the utility of circulating MDH1 and RNH1 biomarkers for determining the prognosis of patients with IDH-wildtype GB. Furthermore, the pathways driven by these biomarkers, and the tumor FABP7 pathway, may constitute promising therapeutic targets for blocking ROS detoxification to overcome resistance to chemoradiotherapy in potential GB STS.
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2020-11-25 | E-MTAB-9849 | biostudies-arrayexpress
Project description:The tumor stage, size, grade, and necrosis (SSIGN) score was originally defined using patients treated with radical nephrectomy (RN) between 1970 and 1998 for clear cell renal cell carcinoma (ccRCC), excluding patients treated with partial nephrectomy (PN).To characterize the original SSIGN score cohort with longer follow-up and evaluate a contemporary series of patients treated with RN and PN.Retrospective single-institution review of 3600 consecutive surgically treated ccRCC patients grouped into three cohorts: original RN, contemporary (1999-2010) RN, and contemporary PN.RN or PN.The association of the SSIGN score with risk of death from RCC was assessed using a Cox proportional hazards regression model, and predictive ability was summarized with a C-index.The SSIGN scores differed significantly between the original RN, contemporary RN, and contemporary PN cohorts (p<0.001), with SSIGN ?4 in 53.5%, 62.7%, and 4.7%, respectively (p<0.001). The median durations of follow-up for these groups were 20.1, 9.2, and 7.6 yr, respectively. Each increase in the SSIGN score was predictive of death from RCC (hazard ratios [HRs]: 1.41 for original RN, 1.37 for contemporary RN, and 1.70 for contemporary PN; all p<0.001). The C-indexes for these models were 0.82, 0.84, and 0.82 for original RN, contemporary RN, and contemporary PN, respectively. After accounting for an era-specific improvement in survival among RN patients (HR: 0.53 for contemporary vs original RN; p<0.001), the SSIGN score remained predictive of death from RCC (HR: 1.40; p<0.001).The SSIGN score remains a useful prediction tool for patients undergoing RN with 20-yr follow-up. When applied to contemporary RN and PN patients, the score retained strong predictive ability. These results should assist in patient counseling and help guide surveillance for ccRCC patients treated with RN or PN.We evaluated the validity of a previously described tool to predict survival following surgery in contemporary patients with kidney cancer. We found that this tool remains valid even when extended to patients significantly different than were initially used to create the tool.
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Project description:Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer
| PRJNA631980 | ENA