Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Thompson JK
PROVIDER: S-EPMC8715475 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma.
Thompson Joyce K JK Bednar Filip F
Epigenomes 20210927 4
Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor's intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic ...[more]
Similar Datasets
Project description:BackgroundThe Ras Association Domain Family Member 1 (RASSF1) is one of the most frequently reported methylation-inactivated tumor suppressor genes in primary pancreatic ductal adenocarcinomas (PDAC). Limited information is still available about the impact of RASSF1 gene silencing on the expression of its different isoforms in neoplastic cells.MethodsA series of 96 primary PDAC, with known clinico-pathological parameters, was tested for RASSF1 methylation status by methylation-specific PCR, RASSF1 locus copy number alterations by fluorescence in situ hybridization, and Rassf1a protein expression by immunohistochemistry. A further series of 14 xenografted primary PDAC and 8 PDAC-derived cell lines were tested to obtain a detailed methylation mapping of CpG islands A and C of the RASSF1 locus by pyrosequencing and to evaluate the expression of Rassf1 variants by qRT-PCR.ResultsMethylation of CpG island A of the RASSF1 gene was observed in 35% of the tumors and allelic loss of RASSF1 locus was seen in 30 disomic and in 20 polysomic cases (52%). Rassf1a immunohistochemical expression was downregulated in half of primary PDAC, and this downregulation was neither correlated with methylation of RASSF1 promoter nor with RASSF1 copy number alterations. RASSF1 status did not influence patients' prognosis. The expression of the seven RASSF1 isoforms in xenografts and cell lines showed that RASSF1A, RASSF1B, and RASSF1C isoforms were present in all xenografts and cell lines, whereas RASSF1D, RASSF1E, and RASSF1F isoforms were variably expressed among samples. RASSF1G was never expressed in either xenografts or cell lines. The variable expression of RASSF1 isoforms in PDAC xenografts and cell lines was not dependent on RASSF1 methylation status of CpG islands A and C.ConclusionsRASSF1 alterations occurring in PDAC mainly consist in variations of expression of the different isoforms. Different genetic mechanisms seem to contribute to RASSF1 deregulation in this setting, but RASSF1 methylation does not seem to substantially affect RASSF1 isoforms expression.
| S-EPMC4710004 | biostudies-literature
Project description:ObjectivesPancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment (TME). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity.MethodsIn vitro human PDAC cell lines MiaPaca2 and S2-013 were treated with 5μ m 3-Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 μ m 5-Azacytidine (5-AZA, a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56/BL7 mice were treated with anti-PD-L1 combined with DZNep and 5-AZA. Short hairpin knockdown (KD) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment (DZNep and 5-AZA). qRT-PCR and microarray assays were performed for the evaluation of Th1-attracting chemokines and cancer-associated antigen induction.ResultsDrug treatments induced significant upregulation of gene expressions of Th1-attracting chemokines, CXCL9 and CXCL10, and the cancer-testis antigens, NY-ESO-1, LAGE and SSX-4 (P < 0.05). In orthotopic tumour models, inoculation of PAN02 cells or KPC cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic Pan02-KD model, the anti-PD-L1 treatment also caused significant tumour regression.ConclusionWe demonstrate that immunotherapy for PDAC can be potentiated with epigenetic therapy by increasing cancer-associated antigen expression and increased T-cell trafficking across the immunosuppressive tumour microenvironment via upregulation of the repressed chemokines and increased apoptosis with subsequent tumour regression.
| S-EPMC9705274 | biostudies-literature
Project description:Gastric cancer is one of the most commonplace and lethal cancers in the world. Molecular investigation of this disease, in order to obtain diagnostic and treatments achievements is important and vital. Relatively, in this research study, one of the most important epigenetic factors, the methylation of CDX2 gene was investigated in tumoral and non-tumoral tissues of gastric cancer patients by bisulfite treatment followed by sequencing of the 5'UTR region of CDX2 in both tissues. The results indicated a hypomethylation in tumoral tissues of adenocarcinoma. Consequently, the methylation amount of CDX2 in tumoral tissues was significantly reduced compared with non-tumoral tissues.
| S-EPMC5143315 | biostudies-literature
Project description:Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR-100-5p is known to be changed in DM patients and can suppress the expression of E-cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E-cadherin and nuclear β-catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin-fixed paraffin-embedded tissue sections. TaqMan miR assays were applied to assess miR-100-5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation-specific polymerase chain reaction. Immunohistochemistry revealed that decreased E-cadherin expression and increased nuclear β-catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long-duration DM (≥3 years) was a significant factor contributing to CDH1 promoter methylation (p < 0.01), while miR-100-5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR-100-5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR-100-5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease-free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis.
| S-EPMC10397378 | biostudies-literature
Project description:Pancreatic adenocarcinoma is a lethal cancer with poor response to chemotherapy and immune checkpoint inhibitors. Recent studies suggest that epigenetic alterations contribute to its aggressive biology and the tumor microenvironment which render it unresponsive to immune checkpoint blockade. Here, we review our current understandings of epigenetic dysregulation in pancreatic adenocarcinoma, its effect on the tumor immune microenvironment, and the potential for epigenetic therapy to be combined with immune checkpoint inhibitors.
| S-EPMC9596544 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies due to its high morbidity and mortality. DNA methylation exerts a vital part in the development of PDAC. However, a mechanistic role of mutual interactions between DNA methylation and mRNA as epigenetic regulators on transcriptomic alterations and its correlation with clinical outcomes such as survival have remained largely uncovered in cancer. Therefore, elucidation of aberrant epigenetic alteration in the development of PDAC is an urgent problem to be solved. In this work, we conduct an integrative epigenetic analysis of PDAC to identify aberrant DNA methylation-driven cancer genes during the occurrence of cancer.MethodsDNA methylation matrix and mRNA profile were obtained from the TCGA database. The integration of methylation and gene expression datasets was analyzed using an R package MethylMix. The genes with hypomethylation/hypermethylation were further validated in the Kaplan-Meier analysis. The correlation analysis of gene expression and aberrant DNA methylation was also conducted. We performed a pathway analysis on aberrant DNG methylation genes identified by MethylMix criteria using ConsensusPathDB.Results188 patients with both methylation data and mRNA data were considered eligible. A mixture model was constructed, and differential methylation genes in normal and tumor groups using the Wilcoxon rank test was performed. With the inclusion criteria, 95 differential methylation genes were detected. Among these genes, 74 hypermethylation and 21 hypomethylation genes were found. The pathway analysis revealed an increase in hypermethylation of genes involved in ATP-sensitive potassium channels, Robo4, and VEGF signaling pathways crosstalk, and generic transcription pathway.ConclusionIntegrated analysis of the aberrant epigenetic alteration in pancreatic ductal adenocarcinoma indicated that differentially methylated genes could play a vital role in the occurrence of PDAC by bioinformatics analysis. The present work can help clinicians to elaborate on the function of differentially methylated expressed genes and pathways in PDAC. CDO1, GJD2, ID4, NOL4, PAX6, TRIM58, and ZNF382 might act as aberrantly DNA-methylated biomarkers for early screening and therapy of PDAC in the future.
| S-EPMC6949667 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by extensive resistance to conventional therapies, making clinical management a significant challenge. As cancer progresses, developmental signals are often aberrantly re-activated, driving the self-renewal of cancer cells and fueling therapy resistance. To understand the epigenetic regulators that may be required to sustain these aggressive cells, we carried out a focused screen and identified SMARCD3 as a new functional dependency in pancreatic cancer. SMARCD3, a subunit of the SWI/SNF nucleosome remodeling complex, was uniquely up-regulated in PDAC stem cells and amplified in human cancer. Using a dual-recombinase model of pancreatic cancer, we showed that stage-specific conditional genetic deletion of Smarcd3 preferentially impaired growth of established tumors, improving survival and synergizing with chemotherapy. Consistent with this, SMARCD3 was required for the in vivo propagation of patient-derived xenografts. Mechanistically, we found that SMARCD3 is incorporated in the BAF complex variant of SWI/SNF. Using comprehensive ChIP-seq analysis to map the SMARCD3-dependent epigenome we showed that Smarcd3 inhibition drives global losses in histone acetylation and BAF binding at active enhancers co-bound by FOXA1. Integrating this with RNA-seq analysis, we found that SMARCD3-BAF regulated a network of genes implicated in diverse programs converging on lipid homeostasis. Specifically, Smarcd3 deletion in vivo inhibited fatty acid metabolism, which is known to be enriched within therapy-resistant cancer cells. These data collectively identify SMARCD3 as a critical dependency in PDAC and link SWI/SNF with the epigenetic control of cell state and metabolism in PDAC.
2022-11-18 | MSV000090744 | MassIVE
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is distinguished by rapid dissemination. Thus, genetic and/or epigenetic deregulation of metastasis suppressor genes (MSG) is a likely event during early pancreatic carcinogenesis and a potential diagnostic marker for the disease. We investigated 9 known MSGs for their role in the dissemination of PDAC and examined their promoters for methylation and its use in PDAC detection.MethodsMRNA expression of 9 MSGs was determined in 18 PDAC cell lines by quantitative RT-PCR and promoter methylation was analyzed by Methylation Specific PCR and validated by Bisulfite Sequencing PCR. These data were compared to the cell lines' in vivo metastatic and invasive potential that had been previously established. Statistical analysis was performed with SPSS 20 using 2-tailed Spearman's correlation with P < 0.05 being considered significant.ResultsComplete downregulation of MSG-mRNA expression in PDAC cell lines vs. normal pancreatic RNA occurred in only 1 of 9 investigated genes. 3 MSGs (CDH1, TIMP3 and KiSS-1) were significantly methylated. Methylation only correlated to loss of mRNA expression in CDH1 (P < 0.05). Bisulfite Sequencing PCR showed distinct methylation patterns, termed constant and variable methylation, which could distinguish methylation-regulated from non methylation-regulated genes. Higher MSG mRNA-expression did not correlate to less aggressive PDAC-phenotypes (P > 0.14).ConclusionsGenes with metastasis suppressing functions in other tumor entities did not show evidence of assuming the same role in PDAC. Inactivation of MSGs by promoter methylation was an infrequent event and unsuitable as a diagnostic marker of PDAC. A distinct methylation pattern was identified, that resulted in reduced mRNA expression in all cases. Thus, constant methylation patterns could predict regulatory significance of a promoter's methylation prior to expression analysis and hence present an additional tool during target gene selection.
| S-EPMC3670210 | biostudies-literature
Project description:Pancreatic cancer (PC) is the most lethal human cancer, with less than 10% 5-year survival. Pancreatic premalignancy is a genetic and epigenomic disease and is linked to PC initiation. Pancreatic premalignant lesions include pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), with pancreatic acinar-to-ductal metaplasia (ADM) as the major source of pancreatic premalignant lesions. Emerging evidence reveals that an epigenetic dysregulation is an early event in pancreatic tumorigenesis. The molecular mechanisms of epigenetic inheritance include chromatin remodeling; modifications in histone, DNA, and RNA; non-coding RNA expression; and alternative splicing of RNA. Changes in those epigenetic modifications contribute to the most notable alterations in chromatin structure and promoter accessibility, thus leading to the silence of tumor suppressor genes and/or activation of oncogenes. The expression profiles of various epigenetic molecules provide a promising opportunity for biomarker development for early diagnosis of PC and novel targeted treatment strategies. However, how the alterations in epigenetic regulatory machinery regulate epigenetic reprogramming in pancreatic premalignant lesions and the different stages of their initiation needs further investigation. This review will summarize the current knowledge of epigenetic reprogramming in pancreatic premalignant initiation and progression, and its clinical applications as detection and diagnostic biomarkers and therapeutic targets in PC.
| S-EPMC9978013 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a disease characterized by extensive resistance to conventional therapies, making clinical management a significant challenge. As cancer progresses, developmental signals are often aberrantly re-activated, driving the self-renewal of cancer cells and fueling therapy resistance. To understand the epigenetic regulators that may be required to sustain these aggressive cells, we carried out a focused screen and identified SMARCD3 as a new functional dependency in pancreatic cancer. SMARCD3, a subunit of the SWI/SNF nucleosome remodeling complex, was uniquely up-regulated in PDAC stem cells and amplified in human cancer. Using a dual-recombinase model of pancreatic cancer, we showed that stage-specific conditional genetic deletion of Smarcd3 preferentially impaired growth of established tumors, improving survival and synergizing with chemotherapy. Consistent with this, SMARCD3 was required for the in vivo propagation of patient-derived xenografts. Mechanistically, we found that SMARCD3 is incorporated in the BAF complex variant of SWI/SNF. Using comprehensive ChIP-seq analysis to map the SMARCD3-dependent epigenome we showed that Smarcd3 inhibition drives global losses in histone acetylation and BAF binding at active enhancers co-bound by FOXA1. Integrating this with RNA-seq analysis, we found that SMARCD3-BAF regulated a network of genes implicated in diverse programs converging on lipid homeostasis. Specifically, Smarcd3 deletion in vivo inhibited fatty acid metabolism, which is known to be enriched within therapy-resistant cancer cells. These data collectively identify SMARCD3 as a critical dependency in PDAC and link SWI/SNF with the epigenetic control of cell state and metabolism in PDAC.
2022-11-18 | MSV000090744 | GNPS