RASSF1A hypermethylation in pretreatment serum DNA of neuroblastoma patients: a prognostic marker.
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ABSTRACT:
SUBMITTER: Misawa A
PROVIDER: S-EPMC2634715 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Circulating tumor DNA (ctDNA) has been used for disease monitoring in several types of cancer. The aim of our study was to investigate whether ctDNA can be used for response monitoring in neuroblastoma. One hundred forty-nine plasma samples from 56 patients were analyzed by quantitative polymerase chain reaction (qPCR) for total cell free DNA (cfDNA; albumin and β-actin) and ctDNA (hypermethylated RASSF1A). ctDNA results were compared with mRNA-based minimal residual disease (qPCR) in bone marrow (BM) and blood and clinical patient characteristics. ctDNA was detected at diagnosis in all patients with high-risk and stage M neuroblastoma and in 3 of 7 patients with localized disease. The levels of ctDNA were highest at diagnosis, decreased during induction therapy, and not detected before or after autologous stem-cell transplantation. At relapse, the amount of ctDNA was comparable to levels at diagnosis. There was an association between ctDNA and blood or BM mRNA, with concordant results when tumor burden was high or no tumor was detected. The discrepancies indicated either low-level BM infiltration (ctDNA negative/mRNA positive) or primary tumor/soft tissue lesions with no BM involvement (ctDNA positive/mRNA negative). ctDNA can be used for monitoring disease in patients with neuroblastoma. In high-risk patients and all patients with stage M at diagnosis, ctDNA is present. Our data indicate that at low tumor load, testing of both ctDNA and mRNA increases the sensitivity of molecular disease monitoring. It is likely that ctDNA can originate from both primary tumor and metastases and may be of special interest for disease monitoring in patients who experience relapse in other organs than BM.
| S-EPMC7446415 | biostudies-literature
Project description:AimTo evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal adenocarcinoma.MethodsMethylation-specific polymerase chain reaction (MSPCR) was used to examine the promoter methylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal disease (30 with benign gastric disease and 30 with benign colorectal disease), and 30 healthy donor controls. A paired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postoperative serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent surgical therapy.ResultsThe frequencies of detection of serum RASSF1A promoter hypermethylation in gastric (34.0%) and colorectal (28.9%) adenocarcinoma patients were significantly higher than those in patients with benign gastric (3.3%) or colorectal (6.7%) disease or in healthy donors (0%) (P < 0.01). The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis.ConclusionAberrant CpG island methylation within the promoter region of RASSF1A is a promising biomarker for gastric and colorectal cancer.
| S-EPMC2712178 | biostudies-literature
Project description:BackgroundMany studies have shown the link between the pretreatment serum transthyretin and prognosis in gastrointestinal (GI) cancers. However, based on the conclusion, the initial findings were inconsistent. Hence, this meta-analysis was performed to identify the prognostic values of the pretreatment serum transthyretin in GI cancers.MethodsPrevious studies published before November 2018 were collected from a comprehensive literature search of several databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were applied in the assessment of the intensity of associations. Also, the publication bias and the robustness of merged data were assessed. All statistical analyses were undertaken using STATA/SE 14.1.ResultsThe combined data indicated that the pretreatment serum transthyretin level was related to the prognosis in GI cancers. The group with reduced pretreatment transthyretin had a significantly worse overall survival (OS) (HR = 1.71, 95% CI: 1.37-2.05). The subgroup analysis for OS further showed the predictive value of transthyretin. In addition, the low serum transthyretin level could be an unfavorable factor for recurrence-free survival (RFS) or progression-free survival (PFS) (HR = 1.66, 95% CI: 1.14-2.18) in GI cancers.ConclusionThe low pretreatment serum transthyretin level implies an unfavorable prognosis for patients with GI cancers. The monitoring of pretreatment transthyretin level could contribute to the risk stratification and individualized therapy in GI cancers.
| S-EPMC6589268 | 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:Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC). Serum IgA antibodies against early antigen (EA-IgA) and viral capsid antigen (VCA-IgA) are the most commonly used to screen for NPC in endemic areas. However, the prognostic value of serum EA-IgA and VCA-IgA in patients with NPC is less clear. We hypothesize that serum EA-IgA and VCA-IgA levels have prognostic impact for survival outcomes in NPC patients with undetectable pretreatment EBV (pEBV) DNA. In this series, 334 patients with non-metastatic NPC and undetectable pEBV DNA were included. Serum EA-IgA and VCA-IgA were determined by ELISA. After analysis, serum EA-IgA and VCA-IgA loads correlated positively with T, N, and overall stage (all P < 0.05). Serum EA-IgA was not associated with survival outcome in univariable analyses. But patients with serum VCA-IgA >1:120 had significantly inferior 5-year progression-free survival (80.4% vs 89.6%, P = 0.025), distant metastasis-free survival (88.4% vs 94.8%, P = 0.050), and locoregional relapse-free survival (88.4% vs 95.6%, P = 0.023; log-rank test). Multivariable analyses revealed that N stage was the only independent prognostic factor (all P < 0.05), but the VCA-IgA became insignificant. Further analyses revealed that serum VCA-IgA was not an independent prognostic factor in early N (N0-1) or advanced N (N2-3) stage NPC. In summary, although both EA-IgA and VCA-IgA correlate strongly with TNM stage, our analyses do not suggest that these antibodies are prognostic biomarkers in patients with NPC and undetectable pEBV DNA.
| S-EPMC5543490 | biostudies-literature
Project description:The pseudomalignant nature of the placenta prompted us to search for tumor suppressor gene hypermethylation, a phenomenon widely reported in cancer, in the human placenta. Nine tumor suppressor genes were studied. Hypermethylation of the Ras association domain family 1 A (RASSF1A) gene was found in human placentas from all three trimesters of pregnancy but was absent in other fetal tissues. Hypermethylation of Rassf1 was similarly observed in placentas from the rhesus monkey but not the mouse. An inverse relationship between RASSF1A promoter methylation and gene expression was demonstrated by bisulfite sequencing of microdissected placental cells and immunohistochemical staining of placental tissue sections using an anti-RASSF1A antibody. Treatment of choriocarcinoma cell lines, JAR and JEG3, by 5-aza-2'-deoxycytidine and trichostatin A led to reduction in RASSF1A methylation but increased expression. These observations extend the analogy between the primate placenta and malignant tumors to the epigenetic level.
| S-EPMC1864885 | biostudies-other
Project description:Because there are few studies regarding the clinical impact of circulating EBV-DNA in peripheral T-cell lymphomas (PTCLs), we tried to evaluate the role of EBV-DNA in whole blood as a prognostic factor for PTCL. We retrospectively reviewed 110 PTCL patients with median age of 63 (20-94) years. Forty-seven patients (42.7%) showed positive results for EBV-DNA, and these patients also had stage III/IV disease, elevated lactic dehydrogenase, and low albumin level (P = 0.007, P = 0.004, P = 0.002, respectively). The 5-year overall survival (OS) and progression free survival (PFS) were 21.0% and 18.0%. Univariable analysis showed that positive EBV-DNA was related with inferior OS and PFS (P = 0.015 and P < 0.001, respectively). Multivariable analysis showed that poor performance status, extranodal involvement more than one site and positive EBV-DNA results were related with OS and PFS (P < 0.001, P < 0.001, P = 0.007 and P = 0.001, P = 0.002, P < 0.001, respectively). Using these three variables, we made a new prognostic model which classified patients on risk as follows: low, no adverse factors; intermediate, 1 factor; or high, 2-3 factors. The new prognostic model could stratify the three groups for OS and PFS better than either international prognostic index or prognostic index of PTCL-u, and showed statistical significance in PTCL, not otherwise specified. This study suggests that whole blood EBV-DNA is related with aggressive clinical characteristics and inferior survival. The new prognostic model, which incorporates EBV-DNA, could better stratify PTCL patients.
| S-EPMC5696183 | biostudies-literature
Project description:ContextRetinoic acid receptor responder protein 2 (RARRES2) is a small secreted protein involved in multiple cancers, including adrenocortical carcinoma (ACC). However, discordant tumor and serum RARRES2 levels have been reported in various cancers. The etiology of this discordance is unknown and has not been studied in pair-matched tumor and serum samples.ObjectiveTo determine tissue and serum RARRES2 levels in patients with adrenocortical neoplasm and to elucidate the prognostic implications of RARRES2 levels.Design, settings, and patientsTissue and serum RARRES2 levels were analyzed. A pair-matched analysis was performed to examine tissue and serum RARRES2 from 51 patients with benign adrenocortical tumors and 18 patients with ACC. Overall survival was analyzed based on RARRES2 expression. A mouse xenograft model was used to determine the source of serum RARRES2.ResultsPatients with ACC had decreased tumor RARRES2 gene expression (P < .0001) and increased serum RARRES2 levels (P < .005) as compared with patients with benign adrenocortical tumors. Higher serum RARRES2 levels were associated with improved overall survival (P = .0227). A mouse xenograft model demonstrated that higher tissue RARRES2 expression was associated with higher RARRES2 secretion in the serum and that there was an intrinsic mechanism in maintaining serum RARRES2 homeostasis.ConclusionsSerum and tissue RARRES2 expression levels are paradoxical in patients with ACC. The elevated RARRES2 in patient serum is unlikely to be secreted from tumor cells. Serum RARRES2 may be used as a novel prognostic marker for ACC.
| S-EPMC5010575 | biostudies-literature
Project description:It is still a matter of debate whether detection of Epstein-Barr virus (EBV) DNA in pretreatment serum has clinical implications for diffuse large B-cell lymphoma. For this study, we measured EBV DNA load in pretreatment serum from 127 diffuse large B-cell lymphoma patients without any underlying immunodeficiency to evaluate its effects on clinical manifestations and prognosis. Anthracycline-based chemotherapy in combination with rituximab was given as initial therapy for 119 patients (94%). Epstein-Barr virus DNA was detected in 15 patients (12%), who were older (P = 0.005) and tended to be at a more advanced disease stage (P = 0.053). They showed significantly worse progression-free survival (PFS) and overall survival (OS) than other patients (P < 0.001 each). This effect remained significant (P = 0.004 and P = 0.027, respectively) after adjustment for age, lactate dehydrogenase, performance status, stage, and extranodal sites. The status of EBV-encoded small RNA in situ hybridization was known for 123 patients; 6 of 8 positive patients (75%) and 9 of 115 negative patients (8%) had detectable EBV DNA in pretreatment serum. While patients positive for EBV-encoded small RNA had significantly worse PFS and OS than negative patients (P = 0.001 and P = 0.029, respectively), EBV DNA detection in pretreatment serum was associated with poorer PFS and OS even for the 115 patients negative for EBV-encoded small RNA (P < 0.001 each). These findings suggest that EBV DNA detection in pretreatment serum may have an adverse prognostic impact for patients with diffuse large B-cell lymphoma.
| S-EPMC4714690 | biostudies-other
Project description:Concentrations of cell-free DNA (cfDNA) circulating in blood and its epigenetic variation, such as DNA methylation, may provide useful diagnostic or prognostic information. Long interspersed nuclear element-1 (LINE-1) constitutes approximately 20% of the human genome and its 5'UTR region is CpG rich. Due to its wide distribution, the methylation level of the 5'UTR of LINE-1 can serve as a surrogate marker of global genomic DNA methylation. The aim of the current study was to investigate whether the methylation status of LINE-1 elements in serum cell-free DNA differs between relapsing remitting multiple sclerosis (RRMS) patients and healthy control subjects (CTR). Serum DNA samples of 6 patients and 6 controls were subjected to bisulfite sequencing. The results showed that the methylation level varies among distinct CpG sites in the 5'UTR of LINE-1 repeats and revealed differences in the methylation state of specific sites in this element between patients and controls. The latter differences were largely due to CpG sites in the L1PA2 subfamily, which were more frequently methylated in the RRMS patients than in the CTR group, whereas such differences were not observed in the L1HS subfamily. These data were verified by quantitative PCR using material from 18 patients and 18 control subjects. The results confirmed that the methylation level of a subset of the CpG sites within the LINE-1 promoter is elevated in DNA from RRMS patients in comparison with CTR. The present data suggest that the methylation status of CpG sites of LINE repeats could be a basis for development of diagnostic or prognostic tests.
| S-EPMC5948235 | biostudies-literature