Detection of aberrant methylation of tumor suppressor genes in plasma from cancer patients

Kawasaki, Hiroaki; Igawa, Emi; Kohosozawa, Rie; Kobayashi, M.; Nishiko, Rika; Abé, Hiroyuki

doi:10.1016/j.pmu.2013.04.007

Cited by 10 publications

(13 citation statements)

References 52 publications

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“…This approach was used, to evaluate the overall diagnostic performance of genes which previously had been examined separately as diagnostic markers for pancreatic cancer. The panel was composed of genes previously detected as hypermethylated in plasma/serum and tumour tissue in relation to pancreatic adenocarcinoma ( BNC1 [17, 24, 25], NPTX2 [4, 24–26], PENK [4, 14, 25], CDKN2A [4, 26, 27], RASSF1A [4, 24, 27], SFRP1 ( SARP2 ) [4, 25], APC [24, 27], BRCA1 [28, 29], CDKN2B [28, 30], ESR1 [25, 28], MGMT [24, 28], MLH1 [28, 31] and RARB [28, 32]), genes earlier found to be hypermethylated in pancreatic juice or tumour tissue from patients with pancreatic adenocarcinoma ( BMP3 [24], EYA2 [24], GSTP1 [29], HIC1 [25, 33], SFRP2 [24], TFPI2 [25], VIM [25], NEUROG1 [24, 25], TAC1 [24, 25], CHFR [24] and WNT5a [24, 25]) and genes found based on a pilot study on cell-free DNA hypermethylation in colorectal adenocarcinoma ( ALX4 , MESTv2 , SEPT9v2 and SST ). To our knowledge, this is the first study to examine cell-free DNA hypermethylation in a wide selection of genes by methylation-specific PCR in a large group of patients with either malignant or benign pancreatic disease.…”

Section: Discussionmentioning

confidence: 99%

Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma

et al. 2016

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BackgroundPancreatic 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.MethodsPatients 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.ResultsPatients 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.ConclusionsCell-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.Trial registrationClinicalTrials.gov, NCT02079363 Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0286-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma

et al. 2016

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“…The initial structure of a double-stranded DNA (dsDNA) was generated by the online web server NAFLex, which can provide DNA, RNA, and other nucleic acid structures. Adenomatous polyposis coli (APC) is classified as one of the tumor suppressor genes linked to a variety of cancers, for example, esophageal, stomach, colon, liver, and lung cancer. ,, It has been reported that the APC gene has been found in both serum and plasma . Therefore, the APC gene is a remarkable candidate as a universal cancer biomarker.…”

Section: Methodsmentioning

confidence: 99%

Simulation Studies on Signature Interactions between Cancer DNA and Cysteamine-Decorated AuNPs for Universal Cancer Screening

Phanchai

Srikulwong

Chuaephon

et al. 2022

ACS Appl. Nano Mater.

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In cancer genomes, DNA methylation results in the formation of a distinct methylation landscape (methylscape) characterized by clustered methylation at regulatory regions separated by extensive intergenic tracks of hypomethylated regions. This methylscape is expressed in the majority of cancer types, thus serving as a universal biomarker for cancer. The aim of the present study was to distinguish between normal and cancer DNA on the basis of their distinct methylscapes using cysteamine-capped gold nanoparticles (Cyst/AuNPs). The signature interactions between cancer DNA and the positively charged AuNPs were revealed by molecular dynamics (MD) simulations and density functional theory (DFT) calculations. Our simulations demonstrate that DNA aggregates in aqueous solution in a methylation-dependent manner, due primarily to the increased hydrophobic force caused by the addition of the methyl group. This suggests that the distinct methylscapes of cancer and normal DNA may result in different agglomerations in aqueous solutions. Cyst/AuNP adsorption patterns on normal and cancer DNA aggregates were also observed to be distinct in MgCl2 solution. Using MD simulations, we discovered that the backbone of oligonucleotides plays a significant role in DNA adsorption onto the gold surface. In addition to that, our DFT calculations indicate that 5-methylcytosine (5-mC) adsorbed on the gold surface has a lower adsorption energy in comparison to cytosine, suggesting that 5-mC is a more favorable site for AuNP adsorption. Due to the methylation-dependent adsorption of Cyst/AuNPs on DNA aggregates, this enables the use of Cyst/AuNPs in cancer screening on the basis of the dispersion of AuNPs adsorbed on DNA aggregates, which is consistent with our experimental validation. This work paves the way for the development of a rapid colorimetric AuNP-based biosensor for methylscape detection that could be used for universal cancer screening.

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“…The methylation status of a panel of five tumor suppressor genes ( p16 , p14 , RASSF1A , APC and DCC ) was evaluated by Kawasaki et al in 2013 [ 30 ]. PDAC patients ( n = 47) were compared to patients with other types of cancer ( n = 197).…”

Section: Cell-free Dna Methylation As Diagnostic Biomarkers For Pdacmentioning

confidence: 99%

“…Except for hepatocellular carcinoma where 73.3% of patients had hypermethylated RASSF1A . Hypermethylation of APC , DCC and p14 were also detected in PDAC patients, however less frequent [ 30 ].…”

Section: Cell-free Dna Methylation As Diagnostic Biomarkers For Pdacmentioning

confidence: 99%

Cell-Free DNA Methylation as Blood-Based Biomarkers for Pancreatic Adenocarcinoma—A Literature Update

Henriksen

Thorlacius-Ussing

2021

Epigenomes

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Pancreatic adenocarcinoma has a horrible prognosis, which is partly due to difficulties in diagnosing the disease in an early stage. Additional blood-born biomarkers for pancreatic adenocarcinoma are needed. Epigenetic modifications, as changes in DNA methylation, is a fundamental part of carcinogenesis. The aim of this paper is to do an update on cell-free DNA methylation as blood-based biomarkers for pancreatic adenocarcinoma. The current literature including our studies clearly indicates that cell-free DNA methylation has the potential as blood-based diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. However, still no clinical applicable biomarker for pancreatic adenocarcinoma based on DNA methylation do exist. Further well-designed validation studies are needed.

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Detection of aberrant methylation of tumor suppressor genes in plasma from cancer patients

Cited by 10 publications

References 52 publications

Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma

Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma

Simulation Studies on Signature Interactions between Cancer DNA and Cysteamine-Decorated AuNPs for Universal Cancer Screening

Cell-Free DNA Methylation as Blood-Based Biomarkers for Pancreatic Adenocarcinoma—A Literature Update

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