Genome-wide Methylation Patterns in Primary Uveal Melanoma: MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE270084 | GEO | 2024/07/24
REPOSITORIES: GEO
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Project description:Uveal melanoma metastases are lethal and remain incurable. Quantitative proteomic analysis of 53 metastasizing and 47 non-metastasizing primary uveal melanoma (pUM) was pursued for insights into UM metastasis and protein biomarkers. The metastatic status of the pUM specimens was defined based on clinical data, survival histories, prognostic analyses, and liver histopathology. LC MS/MS iTRAQ technology, the Mascot search engine and the UniProt human database were used to identify and quantify pUM proteins relative to normal choroid excised from UM donor eyes containing metastasizing (n=6) and non-metastasizing (n=7) pUM. The determined proteomes of all 100 tumors were very similar, encompassing a total of 3935 pUM proteins. Proteins differentially expressed (DE) (n=402) between metastasizing and non-metastasizing pUM were employed in bioinformatic analyses that predicted significant differences in the immune system between metastasizing and non-metastasizing pUM. Immune proteins (n=778) identified in this study support the immune-suppressive nature and low abundance of immune checkpoint regulators in pUM and suggest CDH1 and HLA-DPA1 as candidates for immune therapy checkpoint blockade. Prediction modeling identified 32 proteins capable of predicting with 93% discriminatory accuracy metastasizing versus non-metastasizing pUM, supporting the potential of protein-based prognostic methods for detecting UM metastasis
2021-05-15 | MSV000087437 | MassIVE
Project description:Metastatic uveal melanoma (MUM) is chemoresistant and usually fatal within one year of diagnosis. There is an urgent need to better understand disease pathogenesis, in order to determine key drivers of the metastatic process that could be effectively targeted by therapy. Gene copy number variations occurring in a rare cohort of 13 metastatic and six matched primary, formalin-fixed, paraffin-embedded uveal melanoma samples were identified using the Affymetrix Genome-Wide Human SNP 6.0 Array. Gross chromosomal abnormalities commonly seen in primary UM and associated with the development of metastasis were observed in the MUMs. The most common CNVs were gene amplifications on chromosome 8q, especially in the region 8q24.3. Interestingly, deletions on chromosome 3 were detected at a lower frequency. Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. No genes were altered being unique to either all PUMs or all MUMs of the pairs, but 135 gene CNVs were consistently shared. Of these genes, 125 were amplifications located on chr. 8q24.3. Five genes in the region 8q24.3 and two genes on chromosome 3 were selected for validation by immunohistochemistry because of their known function in cancer (BCL6, C-MYC, E2F5, PTP4A3, SNAI2, and WISP1), or known importance in UM pathology (BAP1). The functional effect of these CNVs on protein expression was confirmed; amplified genes showed increased expression and deleted genes reduced expression. To conclude, our data demonstrate frequent amplification of chromosome 8q in MUMs, suggesting that genes facilitating the expansion of UM in the metastatic niche occur in this region. Furthermore, validation of a range of amplified 8q genes at the protein level strongly indicates the CNVs may be functional and, contribute to MUM biology. 19 samples in total: 13 metastatic uveal melanoma (MUMs) and in six cases their paired primary UM (PUMs)
2016-05-18 | E-GEOD-69614 | biostudies-arrayexpress
Project description:We aimed to investigate the transcriptional program associated with pimonidazole staining in prostate cancer. A pimonidazole gene signature was identified that showed positive correlation to Ki67 labeling index, indicating increased proliferation in pimonidazole positive tumors. A positive correlation to clinical tumor stage and presence of lymph node metastasis was also found, consistent with associations between pimonidazole staining and clinico-pathological parameters. Moreover, the gene signature was associated with high Gleason score in a validation cohort of 59 patients and showed prognostic impact independent of Gleason score and other clinical markers in a watchful waiting validation cohort of 281 patients. Our work reveals the molecular basis of an aggressive prostate cancer phenotype reflected by pimonidazole staining, and suggests that genes involved in proliferation, DNA repair and hypoxia response contribute to this phenotype.
2015-01-05 | GSE55935 | GEO
Project description:Background: Robust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is important for developing individualized treatment plans. This study was conducted to develop and validate a clinically feasible prognostic classifier based on transcriptome-wide gene expression profiles. Methods: Tumor tissues were collected from 208 OPSCC patients treated at Washington University in St. Louis and 115 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 70) from the TCGA cohort were also included for independent validation. Based on RNA-seq profiling data, Cox proportional hazards regression analysis was performed to identify genes associated with disease outcomes. Then, Lasso-penalized multivariate survival models were constructed to identify biomarker genes for developing a prognostic gene signature. Findings: A 60-gene signature was identified by RNA-seq profiling analysis. Computed risk score of the gene signature was significantly predictive of 5-year overall survival of the training cohort (Hazard ratio (HR) 28.32, P = 4.3E-41). Subgroup analysis stratified by HPV status revealed that the signature was prognostic in HPV-positive OPSCC patients (HR 30.55, P = 7.0E-37) and was independent of clinical features. Importantly, the gene signature was validated in two independent patient cohorts, including the TCGA cohort (HR 3.94, P = 0.0018) and the Vanderbilt cohort (HR 8.50, P = 5.7E-09) for overall survival. Conclusions: The prognostic gene signature is a robust tool for risk stratification of OPSCC patients. The signature remains prognostic among HPV-positive OPSCC patients.
2021-04-13 | GSE171898 | GEO
Project description:Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motives we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified co-regulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B cell and T cell infiltration. We calculated metagenes as surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation associated genes. In multivariate Cox regression analysis the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort (Hazard Ratio (HR) 2.20, 95% confidence interval (CI) 1.40-3.46). The B cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR 0.66, 95% CI 0.46 - 0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high grade tumors (n=286, HR 0.78, 95% CI 0.62-0.98), and a second validation cohort enriched for younger patients (n=302, HR 0.83, 95% CI 0.7-0.97). Thus, we could demonstrate in three cohorts of untreated node-negative breast cancer patients, that the humoral immune system plays a pivotal role for metastasis-free survival of carcinomas of the breast. Experiment Overall Design: Population based N0 untreated breast cancer cohort study including 200 samples
2008-10-21 | E-GEOD-11121 | biostudies-arrayexpress
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1?mg/dL) and platelet count (<100?000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10?years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8?years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. 145 liver tissue needle biopsy specimens from U.S. HCV cirrhosis cohort patients with histologically proven cirrhosis lacking evidence and a history of hepatic decompensation or HCC.
2014-08-22 | E-GEOD-54100 | biostudies-arrayexpress
Project description:OBJECTIVE: The number of patients with HCV-related cirrhosis is increasing, leading to a rising risk of complications and death. Prognostic stratification in patients with early-stage cirrhosis is still challenging. We aimed to develop and validate a clinically useful prognostic index based on genomic and clinical variables to identify patients at high risk of disease progression. DESIGN: We developed a prognostic index, comprised of a 186-gene signature validated in our previous genome-wide profiling study, bilirubin (>1 mg/dL) and platelet count (<100 000/mm3), in an Italian HCV cirrhosis cohort (training cohort, n=216, median follow-up 10 years). The gene signature test was implemented using a digital transcript counting (nCounter) assay specifically developed for clinical use and the prognostic index was evaluated using archived specimens from an independent cohort of HCV-related cirrhosis in the USA (validation cohort, n=145, median follow-up 8 years). RESULTS: In the training cohort, the prognostic index was associated with hepatic decompensation (HR=2.71, p=0.003), overall death (HR=6.00, p<0.001), hepatocellular carcinoma (HR=3.31, p=0.001) and progression of Child-Turcotte-Pugh class (HR=6.70, p<0.001). The patients in the validation cohort were stratified into high-risk (16%), intermediate-risk (42%) or low-risk (42%) groups by the prognostic index. The high-risk group had a significantly increased risk of hepatic decompensation (HR=7.36, p<0.001), overall death (HR=3.57, p=0.002), liver-related death (HR=6.49, p<0.001) and all liver-related adverse events (HR=4.98, p<0.001). CONCLUSIONS: A genomic and clinical prognostic index readily available for clinical use was successfully validated, warranting further clinical evaluation for prognostic prediction and clinical trial stratification and enrichment for preventive interventions. 90 liver tissue needle biopsy specimens from patients with histologically proven cirrhosis lacking evidence and a history of hepatic decompensation or HCC.
2014-08-22 | E-GEOD-54099 | biostudies-arrayexpress
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:Genome wide DNA methylation profiling of Stage I Lung Adenocarcinoma and non-tumor adjacent tissues. The Illumina Infinium 27k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across approximately 27,000 CpGs. Samples included tumor and adjacent non-tumor tissues excised from a cohort of 35 patients with Stage I Lung Adenocarcinoma. Candidate prognostic biomarkers were validated by pyrosequencing in independent cohorts.
2015-04-30 | GSE63384 | GEO
Project description:Importance: Severe alcoholic hepatitis (AH) is a highly lethal disease with a 3-month mortality up to 50%. Corticosteroids are the current standard of care although nearly 40% of the patients do not respond and accurate pre-treatment predictors of survival are lacking. Objective: To develop a prognostic score based on molecular and clinical variables before initiation of corticosteroids. Design, Setting, and Participants: Gene expression profiling of fixed liver biopsy obtained for diagnosis of severe AH assessed in 3 independent cohorts (1 prospective cohort for prognostic gene signature and integrative score derivation, and 2 retrospective cohorts for validation). Samples were obtained from 4 European and 1 US medical centers between July 2006 and February 2015. Exposures: Biopsy proven severe AH patients treated with corticosteroids. Main Outcome Measures: Identification of a gene signature combined with a validated clinical index to develop an integrative prognostic score of survival without death or liver transplantation in a derivation cohort (n=71). Prognostic performance of the score was validated in an independent multi-center validation cohort 1 (n=48). Finally, the score was implemented in an FDA-approved clinical diagnostic platform (NanoString) and tested in another independent validation cohort 2 (n=20). Results: A prognostic score, integrating a 123-gene signature and the model for end-stage liver disease (gs-MELD score), was defined in the derivation cohort, in which poor- and good-prognosis patients were discriminated with a cut-off value of 2.66 at 3 months (event-free survival rates of 32% vs. 76%, respectively, p<.001) and 6 months (26% vs. 65%, respectively, p<.001). In the validation cohort 1, the score similarly discriminated poor- and good-prognosis patients at 3 months (43%, [95% CI, 26%-70%] vs. 96% [95% CI, 89%-100%], respectively, p<.001, c-index of 0.83 [95% CI, 0.66-0.99]) and 6 months (34% [95% CI, 18%-61%] vs 84% [95% CI, 72%-100%], respectively, p<.001, c-index of 0.80 [95% CI, 0.66-0.94]), and outperformed other existing clinical indices. The NanoString-based gs-MELD score remained predictive of 3- (p=.03) and 6-month (p=.009) even-free survival in the validation cohort 2. Conclusion and Relevance: The gs-MELD score, incorporating clinically applicable gene signature test and the MELD score, enables pre-treatment survival prediction in severe AH patients.
2018-02-18 | GSE95246 | GEO