Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma.
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ABSTRACT:
SUBMITTER: Stubbe BE
PROVIDER: S-EPMC8616084 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pancreatic cancer has a 5-year survival rate of only 5-7%. Difficulties in detecting pancreatic cancer at early stages results in the high mortality and substantiates the need for additional diagnostic tools. Surgery is the only curative treatment and unfortunately only possible in localized tumours. A diagnostic biomarker for pancreatic cancer will have a major impact on patient survival by facilitating early detection and the possibility for curative treatment. DNA promoter hypermethylation is a mechanism of early carcinogenesis, which can cause inactivation of tumour suppressor genes. The aim of this study was to examine promoter hypermethylation in a panel of selected genes from cell-free DNA, as a diagnostic marker for pancreatic adenocarcinoma.Patients with suspected or biopsy-verified pancreatic cancer were included prospectively and consecutively. Patients with chronic/acute pancreatitis were included as additional benign control groups. Based on an optimized accelerated bisulfite treatment protocol, methylation-specific PCR of a 28 gene panel was performed on plasma samples. A diagnostic prediction model was developed by multivariable logistic regression analysis using backward stepwise elimination.Patients with pancreatic adenocarcinoma (n?=?95), chronic pancreatitis (n?=?97) and acute pancreatitis (n?=?59) and patients screened, but negative for pancreatic adenocarcinoma (n?=?27), were included. The difference in mean number of methylated genes in the cancer group (8.41 (95% CI 7.62-9.20)) vs the total control group (4.74 (95% CI 4.40-5.08)) was highly significant (p?<?0.001). A diagnostic prediction model (age >65, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) had an area under the curve of 0.86 (sensitivity 76%, specificity 83%). The model performance was independent of cancer stage.Cell-free DNA promoter hypermethylation has the potential to be a diagnostic marker for pancreatic adenocarcinoma and differentiate between malignant and benign pancreatic disease. This study brings us closer to a clinical useful diagnostic marker for pancreatic cancer, which is urgently needed. External validation is, however, required before the test can be applied in the clinic.ClinicalTrials.gov, NCT02079363.
| S-EPMC5112622 | biostudies-literature
Project description:IntroductionCurrent prognostic blood-based biomarkers for pancreatic adenocarcinoma (PDAC) are limited. Recently, promoter hypermethylation of SFRP1 (phSFRP1) has been linked to poor prognosis in patients with gemcitabine-treated stage IV PDAC. This study explores the effects of phSFRP1 in patients with lower stage PDAC.MethodsBased on a bisulfite treatment process, the promoter region of the SFRP1 gene was analyzed with methylation-specific PCR. Kaplan-Meier curves, log-rank tests, and generalized linear regression analysis were used to assess restricted mean survival time survival at 12 and 24 months.ResultsThe study included 211 patients with stage I-II PDAC. The median overall survival of patients with phSFRP1 was 13.1 months, compared to 19.6 months in patients with unmethylated SFRP1 (umSFRP1). In adjusted analysis, phSFRP1 was associated with a loss of 1.15 months (95%CI -2.11, -0.20) and 2.71 months (95%CI -2.71, -0.45) of life at 12 and 24 months, respectively. There was no significant effect of phSFRP1 on disease-free or progression-free survival. In stage I-II PDAC, patients with phSFRP1 have worse prognoses than patients with umSFRP1.DiscussionResults could indicate that the poor prognosis may be caused by reduced benefit from adjuvant chemotherapy. SFRP1 may help guide the clinician and be a possible target for epigenetically modifying drugs.
| S-EPMC10272559 | biostudies-literature
Project description:BackgroundTransmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) is a transmembrane protein in the tomoregulin family. Little research has been performed to determine whether TMEFF2 methylation is a prognostic marker in adult diffuse gliomas.MethodsIn this study, we investigated TMEFF2 expression in surgical glioma tissue samples. In addition, we conducted bisulfite amplicon sequencing (BSAS) and methylation-specific PCR (MSP) to evaluate TMEFF2 methylation in glioblastoma (GBM) cells. Subsequently, we investigated the biological function of TMEFF2 in GBM cells. Moreover, we explored the prognostic significance of TMEFF2 in gliomas by analysing a cohort dataset from TCGA.ResultsImmunohistochemistry analysis of 75 paired glioma tumour and peritumoural tissues demonstrated that glioma tumour tissues expressed lower TMEFF2 levels than peritumoural tissues (P < 0.001). TMEFF2 promoter methylation levels were increased in glioblastoma cells compared with SVG p12 cells (P < 0.001). Inhibition of methylation reduced TMEFF2 methylation and increased its expression in LN229 and T98G cells (P < 0.05). Knockdown of TMEFF2 expression significantly promoted the proliferation of U87MG cells and primary GBM cells (P < 0.05). TMEFF2 methylation is negatively associated with IDH1, ATRX and TP53 mutations, and the subtype of glioma harbouring combined IDH1/ATRX/TP53 mutations was associated with low TMEFF2 methylation levels. Survival analysis confirmed that low TMEFF2 methylation levels are associated with good prognosis in glioma patients.ConclusionsOur results suggest that TMEFF2 DNA methylation might be associated with glioma tumour progression and could serve as a valuable prognostic marker for adult diffuse gliomas.
| S-EPMC7931334 | biostudies-literature
Project description:Background and objectivePancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5-6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type BRCA1 allele in PDAC tumors with a germline BRCA1 (gBRCA1) pathogenic or likely pathogenic variant (P/LPV). Herein, we examine promotor hypermethylation as a "second hit" mechanism in patients with gBRCA1-PDAC.MethodsWe evaluated patients with PDAC who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) somatic and germline testing from an institutional database. DNA isolated from tumor tissue and matched normal peripheral blood were sequenced by MSK-IMPACT. In patients with gBRCA1-PDAC, we examined the somatic BRCA1 mutation status and promotor methylation status of the tumor BRCA1 allele via a methylation array analysis. In patients with sufficient remaining DNA, a second methylation analysis by pyrosequencing was performed.ResultsOf 1012 patients with PDAC, 19 (1.9%) were identified to harbor a gBRCA1 P/LPV. Fifteen patients underwent a methylation array and the mean percentage of BRCA1 promotor methylation was 3.62%. In seven patients in whom sufficient DNA was available, subsequent pyrosequencing confirmed an unmethylated BRCA1 promotor. Loss of heterozygosity was detected in 12 of 19 (63%, 95% confidence interval 38-84) patients, demonstrating loss of heterozygosity is the major molecular mechanism of BRCA1 inactivation in PDAC. Two (10.5%) cases had a somatic BRCA1 mutation.ConclusionsIn patients with gBRCA1-P/LPV-PDAC, loss of heterozygosity is the main inactivating mechanism of the wild-type BRCA1 allele in the tumor, and methylation of the BRCA1 promoter is a distinctly uncommon occurrence.
| S-EPMC9626413 | biostudies-literature
Project description:Objectives: The strategy for the treatment of stage IV gastric cancer remains controversial. The objective of this study was to assess whether tumor resection is beneficial to survival in gastric cancer patients with incurable stage IV disease. Methods: This is a retrospective cohort study of gastric cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Due to the baseline bias, 1:1 propensity score matching (PSM) was used in this cohort. Patients were grouped by treatment, (1) gastrectomy with chemoradiotherapy (CRT), or (2) CRT only, and a Cox proportional hazards regression model was used to identify predictors of survival. Overall survival was compared between the two groups using the Kaplan-Meier method. Result: After propensity score matching, 162 stage IV gastric cancer patients diagnosed from 2010 to 2015 were identified. Among these patients, half underwent gastrectomy with CRT, while the others received CRT only. The median overall survival rates were 22 months from the date of surgery for the gastrectomy with CRT group and 9.0 months for CRT only group. In the multivariable Cox regression analysis, surgery was associated with a significant improvement in overall survival [hazard ratio (HR) of death = 0.31, 95% confidence interval (CI) = 0.21-0.46, P < 0.0001]. Conclusion: In conclusion, stage IV gastric cancer is still a fatal disease. This population-based study found that compared with CRT alone, CRT with gastrectomy may be associated with a survival benefit in patients with metastatic GC. In selected patients' survival can be prolonged when the primary tumor is removed. Prospective, randomized trials are required to determine the best strategy for metastatic GC and to describe the characteristics of the selected patients.
| S-EPMC7198747 | biostudies-literature
Project description:BackgroundPrevious studies comparing primary tumor resection (PTR) to palliative treatment for advanced-stage pancreatic ductal adenocarcinoma (PDA) were limited by strong selection bias. We used multiple methods to control for confounding and selection bias to estimate the effect of PTR on survival for late-stage PDA.MethodsSurveillance, Epidemiology, and End Results (SEER) 18 registry database for 2004 through 2014 was retrieved for the present study. A total of 4322 patients with stage III (AJCC, 6th) PDA were included in this study. Propensity score matching (PSM) was performed to eliminate possible bias. In addition, instrumental variable (IV) analysis was utilized to adjust for both measured and unmeasured confounders.ResultsA total of 4322 patients with stage III PDA including 552 (12.8%) who underwent PTR, 3770 (87.2%) without PTR, were identified. In the multivariable cohort, a clear prognostic advantage of PTR was observed in overall survival (OS) (P?<?0.001) and disease-specific survival (DSS) (P?<?0.001) compared to patients after non-surgery therapy. In the PSM cohort, patients in PTR group showed a better OS and DSS (both P values <?0.001) compared to patients in non-surgery group. The survival benefit of PTR for stage III PDA was not observed in the two-stage residual inclusion (2SRI) model. Estimates based on this instrument indicated that patients treated with PTR had similar OS (P?=?0.448) and DSS (P?=?0.719). In IV analyses stratified by chemotherapy and tumor location, patients undergoing PTR had similar OS and DSS compared to patients in non-surgery group across all subgroups.ConclusionsSurvival with PTR did not differ significantly from palliative treatment in marginal patients with stage III pancreatic adenocarcinoma. High-quality randomized trials are needed to validate these results.
| S-EPMC6676580 | biostudies-literature
Project description:Syncytin-1 is a member of human endogenous retroviral W gene family (HERVW1). Known to be expressed in human placental trophoblast, syncytin-1 protein mediates the fusion of cytotrophoblasts for the formation of syncytiotrophoblasts, the terminally differentiated form of trophoblast lineage. In addition, in vitro studies indicate that syncytin-1 possessed nonfusogenic functions such as those for immune suppression, cell cycle regulation and anti-apoptotic activities. Overexpression of syncytin-1 has been observed in various malignant tissues including breast, endometrial and ovarian cancers. It was reported that syncytin-1 gene expression is associated with dynamic changes of DNA hypomethylation in the 5' LTR. In this study, applying the real-time PCR, Western blot analysis and immunohistochemistry methods, we demonstrate a constitutive expression of syncytin-1 in normal pancreas tissues as well as normal tissues adjacent to cancer lesions. Moreover, a reduced expression is found in the pancreatic adenocarcinoma tissues. The expression levels of syncytin-1 are not correlated with the stage, historical grade and gender, but inversely correlated with patients' age. Furthermore, COBRA and bisulfite sequencing results indicated that the lower expression of syncytin-1 is correlated with the hypermethylation of two CpG dinucleotides in the 5' LTR of syncytin-1 gene. The nonfusogenic function of syncytin-1 in normal pancreas as well as its role(s) in the pathogenesis and progression of pancreatic cancers remains to be investigated. Identification of the two CpG dinucleotides around transcription start site as key epigenetic elements has provided valuable information for further studies on the epigenetic regulation of syncytin-1 in pancreatic cancer cells.
| S-EPMC4521816 | biostudies-literature
Project description:Gemcitabine resistance is currently the main problem of chemotherapy for advanced pancreatic cancer patients. The resistance is thought to be caused by altered drug metabolism or reduced apoptosis of cancer cells. However, the underlying mechanism of Gemcitabine resistance in pancreatic cancer remains unclear. In this study, we established Gemcitabine resistant PANC-1 (PANC-1-GR) cell lines and compared the circular RNAs (circRNAs) profiles between PANC-1 cells and PANC-1-GR cells by RNA sequencing. Differentially expressed circRNAs were demonstrated using scatter plot and cluster heatmap analysis. Gene ontology and pathway analysis were performed to systemically map the genes which are functionally associated to those differentially expressed circRNAs identified from our data. The expression of the differentially expressed circRNAs picked up by RNAseq in PANC-1-GR cells was further validated by qRT-PCR and two circRNAs were eventually identified as the most distinct targets. Consistently, by analyzing plasma samples form pancreatic ductal adenocarcinoma (PDAC) patients, the two circRNAs showed more significant expression in the Gemcitabine non-responsive patients than the responsive ones. In addition, we found that silencing of the two circRNAs could restore the sensitivity of PANC-1-GR cells to Gemcitabine treatment, while over-expression of them could increase the resistance of normal PANC-1 and MIA PACA-2 cells, suggesting that they might serve as drug targets for Gemcitabine resistance. Furthermore, the miRNA interaction networks were also explored based on the correlation analysis of the target microRNAs of these two circRNAs. In conclusion, we successfully established new PANC-1-GR cells, systemically characterized the circRNA and miRNA profiles, and identified two circRNAs as novel biomarkers and potential therapeutic targets for Gemcitabine non-responsive PDAC patients.
| S-EPMC5996282 | biostudies-literature
Project description:BackgroundTherapy resistance remains one of the major challenges to improve the prognosis of patients with pancreatic cancer. Chemoresistant cells, which potentially also display cancer stem cell (CSC) characteristics, can be isolated using the side population (SP) technique. Our aim was to search for a SP in human pancreatic ductal adenocarcinoma (PDAC) and to examine its chemoresistance and CSC(-like) phenotype.MethodsHuman PDAC samples were expanded in immunodeficient mice and first-generation xenografts analyzed for the presence of a Hoechst dye-effluxing SP using flow cytometry (FACS). To investigate chemoresistance of the SP, mice bearing PDAC xenografts were treated with gemcitabine and SP proportion determined. In addition, the SP and the main tumour cell population (MP) were sorted by FACS for RNA extraction to profile gene expression, and for culturing under sphere-forming conditions.ResultsA SP was identified in all PDAC samples, analyzed. This SP was more resistant to gemcitabine than the other tumour cells as examined in vivo. Whole-genome expression profiling of the SP revealed upregulation of genes related to therapy resistance, apoptotic regulation and epithelial-mesenchymal transition. In addition, the SP displayed higher tumourigenic (CSC) activity than the MP as analyzed in vitro by sphere-forming capacity.ConclusionWe identified a SP in human PDAC and uncovered a chemoresistant and CSC-associated phenotype. This SP may represent a new therapeutic target in pancreatic cancer.Trial registrationClinicaltrials.gov NCT00936104.
| S-EPMC3500221 | biostudies-literature
Project description:Weekly gemcitabine therapy is the major treatment offered for patients with pancreatic adenocarcinoma cancer; however, relative resistance of tumor cells to chemotherapy, rapid regrowth, and metastasis are the main causes of death within a year. Recently, the daily continuous administration of chemotherapy in low doses--called metronomic chemotherapy (MC)--has been shown to inhibit primary tumor growth and delay metastases in several tumor types; however, its use as a single therapy is still in question due to its moderate therapeutic benefit. Here, we show that the combination of weekly gemcitabine with MC of the same drug delays tumor regrowth and inhibits metastasis in mice implanted orthotopically with pancreatic tumors. We further demonstrate that weekly gemcitabine, but not continuous MC gemcitabine or the combination of the two drug regimens, promotes rebound myeloid-derived suppressor cell (MDSC) mobilization and increases angiogenesis in this tumor model. Furthermore, Bv8 is highly expressed in MDSCs colonizing pancreatic tumors in mice treated with weekly gemcitabine compared to MC gemcitabine or the combination of the two regimens. Blocking Bv8 with antibodies in weekly gemcitabine-treated mice results in a significant reduction in tumor regrowth, angiogenesis, and metastasis. Overall, our results suggest that pro-tumorigenic effects induced by weekly gemcitabine are mediated in part by MDSCs expressing Bv8. Therefore, both Bv8 inhibition and MC can be used as legitimate 'add-on' treatments for preventing post-chemotherapy pancreatic cancer recurrence, progression, and metastasis following weekly gemcitabine therapy.
| S-EPMC4198746 | biostudies-literature