A new metabolic signature contributes to disease progression and predicts worse survival in melanoma.
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ABSTRACT:
SUBMITTER: Wan M
PROVIDER: S-EPMC8291831 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To identify a melanoma microRNA (miRNA) expression signature that is predictive of outcome and then evaluate its potential to improve risk stratification when added to the standard-of-care staging criteria.Total RNA was extracted from 59 formalin-fixed paraffin-embedded melanoma metastases and hybridized to miRNA arrays containing 911 probes. We then correlated miRNA expression with post-recurrence survival and other clinicopathologic criteria.We identified a signature of 18 miRNAs whose overexpression was significantly correlated with longer survival, defined as more than 18 months post-recurrence survival. Subsequent cross-validation showed that a small subset of these miRNAs can predict post-recurrence survival in metastatic melanoma with an estimated accuracy of 80.2% (95% confidence interval, 79.8-80.6%). In contrast to standard-of-care staging criteria, a six-miRNA signature significantly stratified stage III patients into "better" and "worse" prognostic categories, and a multivariate Cox regression analysis revealed the signature to be an independent predictor of survival. Furthermore, we showed that most miRNAs from the signature also showed differential expression between patients with better and worse prognoses in the corresponding paired primary melanoma.MiRNA signatures have potential as clinically relevant biomarkers of prognosis in metastatic melanoma. Our data suggest that molecularly based models of risk assessment can improve the standard staging criteria and support the incorporation of miRNAs into such models.
| S-EPMC4662869 | biostudies-literature
Project description:Background: Glioma, caused by carcinogenesis of brain and spinal glial cells, is the most common primary malignant brain tumor. To find the important indicator for glioma prognosis is still a challenge and the metabolic alteration of glioma has been frequently reported recently. Methods: In our current work, a risk score model based on the expression of twenty metabolic genes was developed using the metabolic gene expressions in The Cancer Genome Atlas (TCGA) dataset, the methods of which included the cox multivariate regression and the random forest variable hunting, a kind of machine learning algorithm, and the risk score generated from this model is used to make predictions in the survival of glioma patients in the training dataset. Subsequently, the result was further verified in other three verification sets (GSE4271, GSE4412 and GSE16011). Risk score related pathways collected in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were identified using Gene Set Enrichment Analysis (GSEA). Results: The risk score generated from our model makes good predictions in the survival of glioma patients in the training dataset and other three verification sets. By assessing the relationships between clinical indicators and the risk score, we found that the risk score was an independent and significant indicator for the prognosis of glioma patients. Simultaneously, we conducted a survival analysis of the patients who received chemotherapy and who did not, finding that the risk score was equally valid in both cases. And signaling pathways related to the genesis and development of multiple cancers were also identified. Conclusions: In summary, our risk score model is predictive for 967 glioma patients' survival from four independent datasets, and the risk score is a meaningful and independent parameter of the clinicopathological information.
| S-EPMC6930419 | biostudies-literature
Project description:To investigate the prognostic significance of time to recurrence (TTR) for overall survival (OS) and survival after recurrence (SAR) in patients with localized or regionally advanced cutaneous melanoma. A total of 731 cutaneous melanoma patients with an initial diagnosis of 8th American Joint Committee on Cancer (AJCC) clinical stage I-III were included in this study. The prognostic factors associated with OS and SAR were estimated through Kaplan-Meier and Cox regression analysis. Of the total cohort, 329 patients (45%) died, and 418 patients (57%) experienced recurrence. The median follow-up and TTR were 55.6 months and 9.6 months, respectively. A total of 141 patients (19%) experienced recurrence in <6 months, and 277 patients (38%) experienced recurrence in ≥6 months. Patients with stage III and positive lymph node dissection (LND) were more common in the early TTR group than in the late TTR group. Both the OS and SAR rates at 5 years and 10 years in the early TTR group were significantly poorer than those in the late TTR group (P < .001 and P = .008, respectively). Furthermore, early TTR, along with truncal tumor, higher TNM stage and therapeutic variables (extended resection, LND and adjuvant therapy), were significant independent predictors of worse OS and SAR in multivariate analysis (all P < .05). Early TTR predicts worse survival and could be considered an independent prognostic factor for patients with localized or regionally advanced cutaneous melanoma. TTR should be evaluated in all patients with recurrence to guide post-recurrence risk stratification and follow-up schedules.
| S-EPMC8459230 | biostudies-literature
Project description:We sought to develop a sentinel lymph node gene expression signature score predictive of disease recurrence in patients with cutaneous melanoma. Gene expression profiling was performed on SLN biopsies using U133A 2.0 Affymetrix gene chips. The top 25 genes associated with recurrence-free survival (RFS) were selected and a penalized regression function was used to select 12 genes with a non-zero coefficient. A proportional hazards regression model was used to evaluate the association between clinical covariates, gene signature score, and RFS. Among the 45 patients evaluated, 23 (51%) had a positive SLN. Twenty-one (46.7%) patients developed disease recurrence. For the top 25 differentially expressed genes (DEG), 12 non-zero penalized coefficients were estimated (CLGN, C1QTNF3, ADORA3, ARHGAP8, DCTN1, ASPSCR1, CHRFAM7A, ZNF223, PDE6G, CXCL3, HEXIM1, HLA-DRB). This 12-gene signature score was significantly associated with RFS (p < 0.0001) and produced a bootstrap C index of 0.888. In univariate analysis, Breslow thickness, presence of primary tumor ulceration, SLN positivity were each significantly associated with RFS. After simultaneously adjusting for these prognostic factors in relation to the gene signature, the 12-gene score remained a significant independent predictor for RFS (p < 0.0001). This SLN 12-gene signature risk score is associated with melanoma recurrence regardless of SLN status and may be used as a prognostic factor for RFS.
| S-EPMC9599365 | biostudies-literature
Project description:Novel treatment modalities comprising immune checkpoint inhibitors and targeted therapies have revolutionized treatment of metastatic melanoma. Still, some patients suffer from rapid progression and decease within months after a diagnosis of stage IV melanoma. We aimed to assess whether genomic alterations may predict survival after the development of stage IV disease, irrespective of received therapy. We analyzed tumor samples of 79 patients with stage IV melanoma using a custom next-generation gene-sequencing panel, MelArray, designed to detect alterations in 190 melanoma-relevant genes. We classified the patients: first, as short survivors (survival ≤6 months after stage IV disease, n = 22) and long survivors (survival >6 months, n = 57); second, by using a cut-off of one year; and third, by comparing the longest surviving 20 patients to the shortest surviving 20. Among analyzed genes, no individual gene alterations, or combinations of alterations, could be dichotomously associated with survival. However, the cohort's mutational profiles closely matched three known mutational signatures curated by the Catalog of Somatic Mutations in Cancer (COSMIC): UV signature COSMIC_7 (cosine-similarity 0.932), clock-like signature COSMIC_5 (cosine-similarity 0.829), and COSMIC_30 (cosine-similarity 0.726). Patients with UV signature had longer survival compared to patients with clock-like and COSMIC 30 (p < 0.0001). Subgroup dichotomization at 6 months showed that 75% of patients with UV signature survived longer than 6 months, and about 75% of patients with clock-like signature survived less than 6 months after development of stage IV disease. In our cohort, clock-like COSMIC_5 mutational signature predicted poor survival while a UV signature COSMIC_7 predicted longer survival. The prognostic value of mutational signatures should be evaluated in prospective studies.
| S-EPMC10418148 | biostudies-literature
Project description:BackgroundA number of genetic markers linked to familial pulmonary fibrosis predict differential survival in interstitial lung disease (ILD) patients. Although genetic testing is not performed routinely for ILD, family history commonly is obtained and may inform outcome risk.Research questionDoes survival vary between patients with and without self-reported familial pulmonary fibrosis?MethodsFamily history was acquired systematically for consecutive ILD patients who consented to clinical registry enrollment at the University of Texas Southwestern and the University of California at Davis. Patients were stratified by idiopathic pulmonary fibrosis (IPF) and non-IPF ILD diagnosis and were substratified by presence or absence of familial pulmonary fibrosis, defined as one or more additional affected family members. Transplant-free survival was compared using multilevel, mixed-effects Cox proportional hazards regression.ResultsOf the 1,262 patients included, 534 (42%) had IPF ILD and 728 (58%) had non-IPF ILD. Of those with non-IPF ILD, 18.5% had connective tissue disease, 15.6% had chronic hypersensitivity pneumonitis, and 23.5% had unclassifiable ILD. Familial pulmonary fibrosis was reported in 134 IPF ILD patients (25.1%) and 90 non-IPF ILD patients (12.4%). Those with familial IPF showed an 80% increased risk of death or transplantation compared with those with sporadic IPF (hazard ratio [HR], 1.8; 95% CI, 1.37-2.37; P < .001), whereas those with familial non-IPF ILD showed a twofold increased risk compared with their counterparts with sporadic disease (HR, 2.08; 95% CI, 1.46-2.96; P < .001). Outcome risk among those with familial non-IPF ILD was no different than for those with sporadic IPF ILD (HR, 1.27; 95% CI, 0.89-1.84; P = .19).InterpretationPatient-reported familial pulmonary fibrosis is predictive of reduced transplant-free survival in IPF and non-IPF ILD patients. Because survival among patients with familial non-IPF ILD approximates that of sporadic IPF ILD, early intervention should be considered for such patients. Until clinical genetic testing is widely available and provides actionable results, family history should be ascertained and considered in risk stratification.
| S-EPMC8173755 | biostudies-literature
Project description:BackgroundFerroptosis plays a vital role in hepatocellular carcinoma (HCC). CISD1 is known to regulate ferroptosis negatively. However, the correlations of CISD1 to prognosis in HCC and its potential mechanism remain unclear.AimTo investigate the expression level and prognostic value of CISD1 in HCC.MethodsGene expression and clinical data for 33 cancer types in TCGA were downloaded from the UCSC Xena platform. Pan-cancer analysis was performed to determine the expression profile and prognostic value of CISD1 in human cancers. GEO datasets and Human Protein Atlas (HPA) were used to verify the mRNA and protein expression levels. The influence of CISD1 on clinical prognosis in HCC was evaluated using a Kaplan-Meier plotter. The PPI network was constructed using the STRING database and Cytoscape. GO and KEGG pathways were constructed using the "clusterProfiler" R package with the FDR cutoff of 0.05. The methylation at the CISD1 promoter was detected using UALCAN and GEO datasets. The correlations between CISD1 and HCC immune infiltrates were investigated via TIMER.ResultsPan-cancer analysis of TCGA data showed that CISD1 is differentially expressed in multiple tumors. Data of gene expression microarrays reveal that the mRNA expression of CISD1 is higher in HCC than that in normal tissue. The protein level of CISD1, validated by the Human Protein Atlas (HPA) database, was upregulated consistently with mRNA levels in HCC samples. High CISD1 expression was associated with better overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS) in LGG, but with poorer OS, DFS, DSS, and PFS in LIHC. Protein-protein interaction (PPI) analysis and GO/KEGG analysis showed that the PPI network and GO term of CISD1 were mainly associated with energy and iron metabolism. Promoter hypomethylation correlated with overexpression of CISD1. CISD1 expression was positively correlated with infiltrating levels of CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in HCC.ConclusionsThese findings suggest that hypomethylation of the CISD1 promoter increases its expression in HCC. CISD1 is associated with prognosis and immune infiltrating levels of CD8+ T cells, macrophages, neutrophils, and DCs in HCC patients. These findings suggest that CISD1 can be used as a prognostic biomarker for determining prognosis in HCC.
| S-EPMC8933656 | biostudies-literature
Project description:BackgroundGenomic instability due to UV radiation is one of the leading causes for melanoma. Histone acetyltransferase p300 plays an indispensible role in DNA repair and maintenance of genomic integrity. The present study was performed to analyze the correlation between p300 expression, melanoma progression and patient survival.MethodsTissue microarray and immunohistochemical analysis was employed to study the expression of p300 in melanoma patients. A total of 358 melanoma patients (250 primary melanoma and 108 metastatic melanoma) were used for the study. Kaplan-Meier, univariate and multivariate Cox regression analysis, and receiver-operating characteristic curves, were used to elucidate the prognostic significance of p300 expression.ResultsOur results demonstrate that p300 is expressed in both nucleus and cytoplasm but the nuclear expression of p300 is predominant. The progression of disease from dysplastic nevi to primary melanoma and to metastatic melanoma was associated with decreased nuclear and increased cytoplasmic p300 expression. Especially, the loss of nuclear and gain in cytoplasmic p300 was correlated with the progression of melanoma from AJCC stage II to stage III, which requires the migration and metastasis of cancer cells from primary sites to lymph nodes. Similarly, decrease in nuclear, and increase in cytoplasmic p300 expression correlated with worse survival of melanoma patients. Nuclear p300 but not cytoplasmic p300 could predict the patient survival independent of AJCC stage, age and gender.ConclusionLoss of nuclear p300 expression is an indicator of worse patient survival and is an independent prognostic marker for melanoma.
| S-EPMC3787094 | biostudies-literature
Project description:Matrix metalloproteinases (MMPs), endopeptidases with diverse biochemical functions, can promote cancer cell invasion and metastasis by degrading the extracellular matrix. A high matrix metalloproteinase-14 (MMP-14) expression in gastric cancer tissue has been associated with metastasis and poor prognosis. To further understand this association, we investigated serum MMP-14 as a biomarker in gastric cancer patients. The patient cohort consisted of 240 gastric adenocarcinoma patients who underwent surgery at Helsinki University Hospital, Finland, between 2000 and 2009. We determined the soluble MMP-14 serum levels using an enzyme-linked immunosorbent assay. We then calculated the associations between serum levels and clinicopathologic variables using the Mann-Whitney U-test or the Kruskal-Wallis test. We constructed survival curves using the Kaplan-Meier method and calculating the hazard ratios using the Cox proportional hazard model. We revealed a positive association between a high serum MMP-14 level and stages III-IV (p = 0.029), and between a high serum MMP-14 and distant metastasis (p = 0.022). Patients with a low serum MMP-14 had a 5-year disease-specific survival of 49.2% (95% confidence interval [CI] 45.5-52.9), whereas patients with a high serum MMP-14 had a 5-year survival of 22.1% (95% CI 15.2-29.0; p = 0.001). High serum MMP-14 was a statistically significant prognostic factor among patients with an intestinal type of cancer (hazard ratio [HR] 3.54; 95% CI 1.51-8.33; p = 0.004), but not among patients with a diffuse type. The serum MMP-14 level remained an independent prognostic factor in our multivariate survival analysis (HR 1.55; 95% CI 1.02-2.35; p = 0.040). This study indicates for the first time that high serum soluble MMP-14 levels in gastric cancer serves as a marker for a poor prognosis, possibly indicating the presence of distant metastases.
| S-EPMC6285995 | biostudies-literature
Project description:There are no reliable criteria to handle disease progression of muscle invasive bladder cancer (MIBC), which strongly influences patient survival. Therefore, an accurate predicting method to identify progressive MIBC patients is greatly needed. The aim of this study was to identify a genetic signature associated with disease progression in MIBC. To address this issue, we analyzed three independent cohorts (a training set, test set 1 and test set 2) comprising a total of 128 MIBC patients. Microarray gene expression profiling, including gene network analysis, was performed in the training set to identify a gene expression signature associated with disease progression. The prognostic value of the signature was validated in test set 1 and test set 2 by microarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The determination of gene expression patterns by microarray data analysis identified 1,320 genes associated with disease progression. Gene network analysis of the 1,320 genes suggested that IL1B, S100A8, S100A9 and EGFR were important mediators of MIBC progression. We validated this putative four-gene signature in two independent cohorts (log-rank test, P < 0.05 each, respectively) and estimated the predictive value of the signature by multivariate Cox regression analysis (hazard ratio [HR], 6.24; 95% confidence interval [CI], 1.58-24.61; P = 0.009). Finally, signature-based stratification demonstrated that the four-gene signature was an independent predictor of MIBC progression. In conclusion, a molecular signature defined by four genes represents a promising diagnostic tool for the identification of MIBC patients at high risk of progression.
| S-EPMC3105150 | biostudies-literature