Prognostic significance of LKB1 promoter methylation in cutaneous malignant melanoma.
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ABSTRACT:
SUBMITTER: Zhang W
PROVIDER: S-EPMC5530115 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:BackgroundEpithelial splicing regulatory protein 1 (ESRP1) has been described as an RNA-binding protein involved in cancer development. However, the expression and regulatory network of ESRP1 in cutaneous malignant melanoma (CMM) remain unclear.MethodsFrom the sequencing data of 103 CMM samples in The Cancer Genome Atlas database, the expression level of ESRP1 and its correlation with the clinicopathological characteristics were analyzed using the Oncomine 4.5, Gene Expression Profiling Interactive Analysis (GEPIA), and UALCAN tools, while LinkedOmics was used to identify differential gene expression with ESRP1 and to analyze Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Gene enrichment analysis examined target networks of kinases, miRNAs, and transcription factors. Finally, TIMER was used to analyze the relationship between ESRP1 and tumor immune cell infiltration.ResultsWe found that ESRP1 was lowly expressed in CMM tissues, and a low level of ESRP1 expression correlated with better overall survival. Expression of this gene was linked to functional networks involving the condensed chromosomes, epidermal development, and translation initiation. Functional network analysis suggested that ESRP1 regulated ribosome metabolism, drug metabolism, and chemical carcinogenesis via pathways involving several cancer-related kinases, miRNAs, and transcription factors. Furthermore, our results suggested that ESRP1 played an important role in regulating tumor-associated macrophage polarization, dendritic cell infiltration, Treg cells, and T cell exhaustion.ConclusionOur study demonstrates ESRP1 expression, prognostic value, and potential regulatory networks in CMM, thereby shedding light on the clinical significance of ESRP1, and provides a novel biomarker for determining prognosis and immune infiltration in CMM.
| S-EPMC7492958 | biostudies-literature
Project description:Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples (n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [RAC1, FGFR1, CARD11, CIITA; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1. Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort (n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up (n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable (p = 0.09) and adverse (p = 0.07), respectively]. Somatic mutations in SPEN, and to a lesser extent RAC1, were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity (p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53), such as RAC1 and SPEN, may have prognostic significance in MM.
| S-EPMC6329304 | biostudies-literature
Project description:We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma.
| S-EPMC6347251 | biostudies-literature
Project description:A novel human protoparvovirus related to human bufavirus and preliminarily named cutavirus has been discovered. We detected cutavirus in a sample of cutaneous malignant melanoma by using viral enrichment and high-throughput sequencing. The role of cutaviruses in cutaneous cancers remains to be investigated.
| S-EPMC5324802 | biostudies-literature
Project description:Cutaneous malignant melanoma (CMM) is the most deadly skin cancer worldwide. Despite advances in the treatments of CMM, its incidence and mortality rates are still increasing. N6-methyladenosine (m6A) is the most common form of RNA modification and has attracted increasing interest in cancer initiation and progression. However, the role of m6A regulators in CMM and their correlation with prognosis remain elusive. Here, we demonstrated that by applying consensus clustering, all CMM patient cases can be divided into two clusters based on overall expression levels of 25 m6A genes. We systematically analyzed the prognostic value of the 25 m6A RNA methylation regulators in CMM and found that ELAVL1, ABCF1, and IGF2BP1 yield the highest scores for predicting the prognosis of CMM. Accordingly, we derived a risk signature consisting of three selected m6A genes as an independent prognostic marker for CMM and validated our findings with data derived from a different CMM cohort. Next, we determined that CNVs in m6A genes had a significant negative impact on patient survival. The mRNA expression levels of m6A genes were correlated with CNV mutation. Moreover, in the selected three risk signature m6A regulators, GSEA analysis showed that they were closely correlated with inflammation and immune pathways. TME analysis proved that m6A gene expressions were negatively correlated with immune cell infiltration. In conclusion, m6A regulators are vital participants in CMM pathology; and ELAVL1, ABCF1, and IGF2BP1 mRNA levels are valuable factors for prognosis prediction and treatment strategy development.
| S-EPMC9201746 | biostudies-literature
Project description:BackgroundCutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses.MethodsWe performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry.ResultsWe identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration.ConclusionsOur data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.
| S-EPMC5458482 | biostudies-literature
Project description:Invasive malignant melanoma (MM) usually has a poor prognosis developing visceral disease with no curative therapy available so far. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function is commonly deregulated in different types of cancer. However, little is known on whether and how NCoR loss of function impacts in MM, which might have important diagnostic and prognostic significance. We here show that loss of nuclear NCoR is significantly associated with MM progression, but at comparable stage of the disease is predictive of patient outcome and reduced overall survival. Loss of nuclear NCoR results in upregulation of specific cancer-related genetic signature, whereas inhibition of IKK activity in melanoma cells is reverts both NCoR nuclear distribution and gene transcription. Analysis of public database demonstrated the high prevalence of inactivating NCoR mutations in MM, with characteristics of driver oncogene.
2014-12-31 | GSE56494 | GEO
Project description:Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene.
| S-EPMC4496217 | biostudies-literature
Project description:BACKGROUND:This study aimed to assess the independent prognostic value of tumor size compared with other clinical and pathologic features of primary invasive cutaneous melanoma (CM). METHODS:This study included 28,593 patients with primary invasive CM in Surveillance, Epidemiology, and End Results Program database diagnosed from 2004 through 2016. Tumor size was divided into five subgroups (?6, 7-12, 13-30, 31-42, and >42 mm). The primary endpoint was melanoma-specific survival (MSS). RESULTS:The relationship between tumor size and survival was piecewise. After adjusting for age, sex, primary site, histopathologic cell type, Breslow thickness, ulceration, mitotic rate, regional metastasis, and distant metastasis, the hazard ratio (HR) of MSS increased with increasing tumor size until a peak at 31-42 mm (HRs, 1.33, 1.59, 2.41, respectively; all P < .0001), and then decreased when tumor size was larger than 42 mm using tumor size ? 6 mm as the reference (HR, 2.11; 95% confidence interval [CI], 1.84 -2.42; P < .0001). This pattern mostly remained after stratification by T subcategories from T1 to T4 in localized primary CM except that tumor size >42 mm subgroup had the shortest MSS in T4. In addition, tumor size with a cutoff value of 12 mm showed stronger prognostic value for MSS (HR, 2.32; 95% CI, 1.80-2.98; P < .0001) than Breslow thickness and mitotic rate in primary CM with T1N0M0. CONCLUSIONS:Tumor size was an important independent prognostic factor for MSS in patients with primary invasive CM. Tumor size larger than 30 mm would provide additional and important prognostic information in each T subcategory of localized CM. Furthermore, tumor size with a cutoff value of 12 mm has great potential in improving the accuracy of melanoma T1 substaging.
| S-EPMC7333855 | biostudies-literature
Project description:ImportanceBreslow thickness is a 1-dimensional surrogate prognostic feature for tumor size, yet tissue sections have 2 dimensions. Therefore, a 2-dimensional feature, calculated tumor area (CTA), was devised.ObjectiveTo determine CTA precision and prognostic value.Design, setting, and participantsThis retrospective cohort of patients with cutaneous melanoma presented to the Leicester and Nottingham National Health Service hospital trusts in the United Kingdom. Eligible patients in the Leicester development sample had available primary tumor tissue; a diagnosis from January 1, 2004, through December 31, 2011; invasive disease; and Leicestershire residency. Patients in the Nottingham validation sample had an anonymized spreadsheet with primary melanoma diagnosed from January 1, 2003, through December 31, 2005, or from January 1, 2008, through December 31, 2010. From a starting population of 1463 patients in both data sets, a total of 224 (15.3%) were excluded to yield a study population of 1239. Data were analyzed from April 30, 2018, through January 10, 2019.InterventionAn observational analysis of the prognostic value of CTA in patients with cutaneous melanoma.Main outcomes and measuresIndependent association of CTA with melanoma-specific survival and confounding effect of CTA on Breslow thickness in survival analysis.ResultsA total of 1239 patients with melanoma were assessed, including 649 (52.4%) women, with a median age of 60 years (interquartile range, 47-71 years). An intraclass correlation coefficient for CTA on 13 cases was 0.99. In 918 patients in the Leicester cohort, CTA was an independent prognostic factor in Cox proportional hazards regression models after adjusting for Breslow thickness, age, sex, ulcer, mitotic rate, and microsatellites (hazard ratio [HR], 1.87; 95% CI, 1.49-2.34; P < .001). Validation in 321 patients in the Nottingham cohort showed an HR of 1.55 (95% CI, 1.15-2.09; P = .005) and in the combined 1239 cases, an HR of 1.70 (95% CI, 1.43-2.03; P < .001). Breslow thickness was significant in multivariable analysis only when CTA was not in the model. The relative importance of CTA was shown by its retention in all 100 bootstrap multivariable models with backward selection, whereas Breslow thickness was retained in only 53. Melanomas stratified by CTA showed wider separation of survival curves than those stratified by Breslow thickness using the American Joint Committee on Cancer Staging Manual, 8th Edition (HRs, 1.00 to 41.46 vs 1.00 to 36.95, respectively), and the model with CTA categories had a Bayesian information criterion difference of 13.9 compared with T category, indicating substantially better fit. This model had a Harrell C index of 83.7%, and bootstrap analysis showed little evidence of model optimism, with a corrected calibration slope of 0.99.Conclusions and relevanceThis study provides a novel microscopic feature, CTA, with evidence of its independent prognostic value. This evidence suggests that CTA should be a priority for further study.
| S-EPMC6596334 | biostudies-literature