Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer.
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ABSTRACT:
SUBMITTER: Misawa K
PROVIDER: S-EPMC5041966 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Silencing of tumor suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis and a potential target for personalized cancer treatment. In head and neck cancer, little is known about the role of promoter hypermethylation in survival. Using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) we investigated the role of promoter hypermethylation of 24 well-described genes (some of which are classic TSGs), which are frequently methylated in different cancer types, in 166 HPV-negative early oral squamous cell carcinomas (OSCC), and 51 HPV-negative early oropharyngeal squamous cell carcinomas (OPSCC) in relation to clinicopathological features and survival. Early OSCC showed frequent promoter hypermethylation in RARB (31% of cases), CHFR (20%), CDH13 (13%), DAPK1 (12%), and APC (10%). More hypermethylation (? 2 genes) independently correlated with improved disease specific survival (hazard ratio 0.17, P = 0.014) in early OSCC and could therefore be used as prognostic biomarker. Early OPSCCs showed more hypermethylation of CDH13 (58%), TP73 (14%), and total hypermethylated genes. Hypermethylation of two or more genes has a significantly different effect on survival in OPSCC compared with OSCC, with a trend toward worse instead of better survival. This could have a biological explanation, which deserves further investigation and could possibly lead to more stratified treatment in the future.
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Project description:Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (p < 0.001) and the methylation index of tumor suppressor genes (p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390?3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients.
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Project description:Lecithin:retinol acyltransferase (LRAT) is a major enzyme involved in vitamin A/retinol metabolism, which regulates various physiological processes like cell proliferation and differentiation. LRAT expression is reduced in numerous cancers, yet the underlying mechanisms have remained undefined. We hypothesized that methylation silencing may contribute to decreased LRAT gene expression in colorectal cancer (CRC). LRAT hypermethylation status was analyzed in five CRC cell lines, 167 colorectal tumors, and 69 adjacent normal colonic mucosae, using a quantitative bisulfite/PCR/LDR/Universal Array assay. LRAT transcription levels were determined by real-time RT-PCR in a subset of tumors and matched normal tissues and in CRC cell lines that were treated with a demethylating agent, 5-aza-2'-deoxycytidine. The incidence of LRAT hypermethylation was significantly higher in colorectal tumors than in adjacent normal mucosae (p = 0.0025). Aberrant methylation occurred in 51 % of microsatellite-stable CRCs, in 84 % of microsatellite-unstable CRCs, and in 12 out of 13 colonic polyps. The number of hypermethylated LRAT events was inversely correlated with CRC stage (p < 0.0001). Importantly, LRAT hypermethylation was associated with decreased mRNA level in CRC clinical specimens, and demethylation treatment resulted in LRAT transcriptional reactivation. Our data support the idea that LRAT promoter hypermethylation associates with LRAT gene expression in CRC. The higher frequency of LRAT hypermethylation in colonic polyps and early-stage CRCs indicates that it may occur early in malignant progression.
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Project description:IntroductionThe role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed.MethodsStage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma.ResultsThere were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death.ConclusionsThis study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.
| S-EPMC8974360 | biostudies-literature
Project description:Head and neck cancer (HNC) is the fifth most common cancer worldwide. In this study, we performed an integrative analysis of the discovery set and established an eight-gene signature for the prediction of prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Univariate Cox analysis was used to identify prognosis-related genes (with P < 0.05) in the GSE41613, GSE65858, and TCGA-HNSC RNA-Seq datasets after data collection. We performed LASSO Cox regression analysis and identified eight genes (CBX3, GNA12, P4HA1, PLAU, PPL, RAB25, EPHX3, and HLF) with non-zero regression coefficients in TCGA-HNSC datasets. Survival analysis revealed that the overall survival (OS) of GSE41613 and GSE65858 datasets and the progression-free survival(DFS)of GSE27020 and GSE42743 datasets in the low-risk group exhibited better survival outcomes compared with the high-risk group. To verify that the eight-mRNA prognostic model was independent of other clinical features, KM survival analysis of the specific subtypes with different clinical characteristics was performed. Univariate and multivariate Cox regression analyses were used to identify three independent prognostic factors to construct a prognostic nomogram. Finally, the GSVA algorithm identified six pathways that were activated in the intersection of the TCGA-HNSC, GSE65858, and GSE41613 datasets, including early estrogen response, cholesterol homeostasis, oxidative phosphorylation, fatty acid metabolism, bile acid metabolism, and Kras signaling. However, the epithelial-mesenchymal transition pathway was inhibited at the intersection of the three datasets. In conclusion, the eight-gene prognostic signature proved to be a useful tool in the prognostic evaluation and facilitate personalized treatment of HNSCC patients.
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Project description:Signal transducer and activator of transcription 3 (STAT3) overactivation is a common event in many cancers, including head and neck squamous cell carcinoma (HNSCC), where STAT3 represents a promising therapeutic target. HNSCC is not characterized by frequent kinase mutations, in contrast to some malignancies where mutational activation of kinases upstream of STAT3 is common. Instead, STAT3 may be activated by loss-of-function of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers, including HNSCC (60.1% of tumors analyzed) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression. These findings were confirmed in an independent cohort of HNSCC tumors by methylation-specific PCR and immunohistochemistry. We demonstrate that PTPRT promoter methylation and gene silencing is reversible in HNSCC cells, leading to PTPRT-specific downregulation of pSTAT3 expression. We further show that PTPRT promoter methylation is significantly associated with sensitivity to STAT3 inhibition in HNSCC cells, suggesting that PTPRT promoter methylation may serve as a predictive biomarker for responsiveness to STAT3 inhibitors in clinical development.
| S-EPMC4651851 | biostudies-literature
Project description:PROM1 has played a pivotal role in the identification and isolation of tumor stem cells. This study aimed to assess the association between PROM1 promoter methylation and head and neck squamous cell carcinoma (HNSCC), and its diagnostic and prognostic value.Bioinformatic analysis was performed using data from the Cancer Genome Atlas-HNSC and Gene Expression Omnibus datasets.The results showed that PROM1 promoter was hypermethylated in HNSCCs compared with normal head and neck tissues (P?=?4.58E-37). The area under the receiver-operating characteristic curve based on methylated PROM1 data was 0.799. In addition, PROM1 hypermethylation independently predicted poor overall survival (hazard ratio [HR]: 1.459, 95% confidence interval [CI]: 1.071-1.987, P?=?.016) and recurrence-free survival (HR: 1.729, 95% CI: 1.088-2.749, P?=?.021) in HNSCC patients. Moreover, PROM1 methylation was weakly negatively correlated with its mRNA expression (Pearson r?=?-0.148, P?<?.001).In summary, our study reveals that methylated PROM1 might serve as a valuable diagnostic biomarker and predictor of poor survival for HNSCC patients. PROM1 hypermethylation might partially contribute to its downregulation in HNSCC.
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Project description:BackgroundEpigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor-related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status.MethodologyThe study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex-PCR respectively.Principal findingsUnsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31 genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival.ConclusionsPromoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC.
| S-EPMC4476679 | biostudies-literature
Project description:Majority of patients with resected early- and intermediate-stage liver cancer will experience postoperative recurrence. This study aimed to investigate the application of ctDNA sequencing in the postoperative period of hepatocellular carcinoma. A total of 96 patients with liver cancer were enrolled in this study. Postoperative peripheral blood samples were collected from all patients after surgery and analyzed using hybridization capture-based next-generation sequencing. Identification of at least one somatic mutation in the peripheral blood was defined as ctDNA+. Five genetic features in tumor tissues were associated with disease-free survival (DFS) using Lasso-Cox model. The area under the receiver operating characteristic curve was 0.813 and 0.882 in training and validation cohorts, respectively. The recurrence rate in ctDNA+ and ctDNA- groups was 60.9% and 27.8%, respectively. Multivariate Cox regression analysis showed that the postoperative ctDNA was an independent prognostic predictor of DFS (HR [hazard ratio]: 6.074, 95% Cl [confidence interval]: 2.648-13.929, P<0.001) and overall survival (OS) (HR: 4.829, 95% CI: 1.508-15.466, P=0.008). Combined ctDNA with AFP improved prediction performance. The median DFS was 2.0, and 8.0 months in ctDNA+/AFP-H and ctDNA+/AFP-L groups, respectively; while ctDNA-/AFP-H and ctDNA-/AFP-L groups had not reached the median time statistically (Log-rank test, P < 0.0001). Furthermore, ctDNA- patients had better prognosis than ctDNA+ patients irrespective of tumor stage. Postoperative ctDNA sequencing has great prognostic value in patients with liver cancer. Patients with positive ctDNA should receive more intensive disease monitoring and more aggressive treatment strategies to improve the survival time.
| S-EPMC8931326 | biostudies-literature
Project description:BackgroundThe CAV family, especially CAV1 and CAV2, is significantly associated with tumor development. In this study, we aimed to explore the pathogenic and prognostic roles of CAV1 and CAV2 in head and neck squamous cell carcinoma (HNSCC) through bioinformatic analysis and verified in human tissue.MethodsWe analyzed expression profiles of CAV1 and CAV2 in HNSCC and in normal tissues via data from The Cancer Genome Altas. Prognostic significance was examined by Kaplan-Meier survival curve obtained from the Xena browser together with Cox regression analysis. Co-expressed genes were uploaded to GeneMANIA and applied to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, showing interaction networks. Signaling pathways of CAV1 and CAV2 in HNSCC were analyzed by Gene Set Enrichment Analysis to elucidate potential regulatory mechanisms. Gene-drug interaction network was explored via Comparative Toxicogenomics Database. Immunohistochemistry was performed to verify theoretical results.ResultsCompared with normal tissues, expression levels of CAV1 and CAV2 were remarkably higher in HNSCC (p < 0.0001), which independently implies poor OS (CAV1: HR: 1.146, p = 0.027; CAV2: HR: 1.408, p = 0.002). Co-expressed genes (PXN, ITGA3, TES, and MET) were identified and analyzed by FunRich with CAV1 and CAV2, revealing a significant correlation with focal adhesion (p < 0.001), which has a vital influence on cancer progression. GSEA also showed cellular protein catabolic process (ES = 0.42) and proteasome complex (ES = 0.72), which is a key degradation system for proteins involved in oxidatively damaging and cell cycle and transcription, closely correlated with high expression of CAV2 in HNSCC. More importantly, we found the relationship between different immune cell infiltration degrees in the immune micro-environment in HNSCC and expression levels of CAV1/CAV2 (p < 0.0001). Gene-drug interaction network was checked via CTD. Moreover, tissue microarrays verified higher expression levels of CAV1/CAV2 in HNSCC (p < 0.0001), and the high expression subgroup indicated significantly poorer clinical outcomes (p < 0.05).ConclusionsThe results revealed that CAV1 and CAV2 are typically upregulated in HNSCC and might predict poor prognosis.
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