Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

Guler, Gulfem D.; Ning, Yuhong; Ku, Chin-Jen; Phillips, Tierney; McCarthy, Erin; Ellison, Christopher K.; Bergamaschi, Anna; Collin, François; Lloyd, Paul; Scott, Aaron; Antoine, Michael; Wang, Ke; Chau, Kim; Ashworth, Alan; Quake, Stephen R.; Levy, Samuel

doi:10.1038/s41467-020-18965-w

Cited by 119 publications

(103 citation statements)

References 62 publications

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“…In contrast the hydroxymethylome libraries were more localized to distinct genomic regions and tended to form peaks that could be characterized at both broad and narrow resolution and covered only 31% of the genome with at least one read and ~ 5% at more than ve reads. This is consistent with previous reports describing the genomic distribution of 5hmC 13,15,34 .…”

Section: Study Populationsupporting

confidence: 94%

“…Therefore, there is growing interest in utilizing the epigenome of cfDNA for cancer detection. Several groups have investigated whether cancer can be detected via epigenetic changes in the tumor fraction of cfDNA such as DNA methylation 8,12 , DNA hydroxymethylation [13][14][15] and cfDNA characteristics which may reveal chromatin structure 16 . Methylation of cystosine bases to produce methylcytosine (5mC) is a well-known epigenetic mechanism controlling gene expression.…”

Section: Introductionmentioning

confidence: 99%

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Hydroxymethylation profile of cell free DNA is a biomarker for early colorectal cancer

Walker

Rashid

et al. 2021

Preprint

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Early detection of colorectal cancer (CRC) will improve survival rates. We created a classifier to detect CRC, based on 5-hydroxymethylcytosine levels in cell free DNA isolated from blood samples of 2198 individuals. Our classifier discriminated CRC samples from controls with an area under the receiver operating characteristic curve (AUC) of 90% (sensitivity was 55% at 95% specificity). Performance was similar for early stage 1 (AUC 89%) and late stage 4 CRC (AUC 94%). Performance was independent of the proportion of tumor-DNA in the cell free DNA. We expanded the classifier to include information about cell free DNA fragment size and abundance across the genome. Overall performance was similar (AUC 91%), with gains in sensitivity (63% at 95% specificity). The 5-hydroxymethylcytosine signal allows detection of CRC, even in cell free DNA samples with undetectable tumor DNA. Including 5-hydroxymethylcytosine in multi-analyte screening, will improve sensitivity for early-stage cancer.

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Section: Study Populationsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Hydroxymethylation profile of cell free DNA is a biomarker for early colorectal cancer

Walker

Rashid

et al. 2021

Preprint

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“…The investigation of differential hydroxymethylation in cfDNA was attempted in order to detect early-stage PDAC by determining 5-hydroxymethylcytosine (5hmC) changes. Guller et al compared 5nhC densities in cfDNA from patients with PDAC to non-cancer controls [ 38 ]. They found 5700 hyper- and 6155 hypo-hydroxymethylated genes in 41 PDAC samples compared to 38 non-cancer samples (discovery data set).…”

Section: Circulating Tumor Dnamentioning

confidence: 99%

Molecular Approaches Using Body Fluid for the Early Detection of Pancreatic Cancer

Satoh

2021

Diagnostics

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Pancreatic ductal adenocarcinoma (PDAC) is the most malignant form of gastrointestinal tumor and is the fourth leading cause of deaths due to cancer in Japan. This cancer shows a poor outcome due to the difficulty of its early diagnosis and its rapid growth. Once this disease becomes clinically evident, it is frequently accompanied by distant metastasis at the time of diagnosis. A recent multicenter study in Japan revealed that patients with the early stage of this disease (stage 0 and I) showed favorable prognosis after surgical resection, indicating the importance of early detection for improvement of PDAC prognosis. PDAC develops through a stepwise progression from the precursor lesion, and over the last few decades molecular analyses have shown the detailed genetic alterations that occur in this process. Since advances in molecular technologies have enabled the detection of genetic changes from a very small quantity of samples, a large number of non-invasive molecular approaches have been utilized in an attempt to find precursor or non-invasive carcinoma lesions. In this review, the current efforts in terms of the molecular approaches applied for the early detection of PDAC—especially using body fluids such as pancreatic juice, blood, and saliva—are summarized.

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“…[ 9–11 ] Given its indirect and direct roles in regulating gene expression, 5hmC is now a widely accepted hallmark of numerous diseases, especially cancers. [ 12–14 ]…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Quantification of DNA 5‐Hydroxymethylcytosine Using DNA Hybridization‐Based Single‐Molecule Immunofluorescent Imaging

Lai

Liu

et al. 2021

Small Methods

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5‐Hydroxymethylcytosine (5hmC) is a deoxyribonucleic acid (DNA) epigenetic modification that has an important function in embryonic development and human diseases. However, the numerous methods that have been developed to detect and quantify 5hmC, require large amounts of DNA sample to be modified via chemical reactions, which considerably limits their application with cell‐free DNA (cfDNA). Meanwhile, other antibody‐based methods of detecting 5hmC do not offer information about the DNA sequence. Here, in this article DNA hybridization‐based single‐molecule immunofluorescent imaging is presented, an ultrasensitive method of detecting 5hmC modification in DNA. Via using the probe DNA to capture the DNA fragment of interest and the 5hmC antibody to detect the 5hmC modification in DNA, the fluorescent response signal of the 5hmC modification from the secondary antibody at the single‐molecule level is successfully detected. Using the method, one could determine the quantity of 5hmC in the gene of interest within 6 h. In addition, it requires only 3 pg of the DNA sample and minimal experience and training for operation and analysis.

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Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA

Cited by 119 publications

References 62 publications

Hydroxymethylation profile of cell free DNA is a biomarker for early colorectal cancer

Hydroxymethylation profile of cell free DNA is a biomarker for early colorectal cancer

Molecular Approaches Using Body Fluid for the Early Detection of Pancreatic Cancer

Epigenetic Quantification of DNA 5‐Hydroxymethylcytosine Using DNA Hybridization‐Based Single‐Molecule Immunofluorescent Imaging

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