Dataset Information

Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers' Discovery.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer types world-wide. Its high mortality is related to the difficulty in the diagnosis, which often occurs when the disease is already advanced. As of today, no early diagnostic tests are available, while only a limited number of prognostic tests have reached clinical practice. The main reason is the lack of reliable biomarkers that are able to capture the early development or the progression of the disease. Hence, the discovery of biomarkers for early diagnosis or prognosis of PDAC remains, de facto, an unmet need. An increasing number of studies has shown that cell-free DNA (cfDNA) methylation analysis represents a promising non-invasive approach for the discovery of biomarkers with diagnostic or prognostic potential. In particular, cfDNA methylation could be utilized for the identification of disease-specific signatures in pre-neoplastic lesions or chronic pancreatitis (CP), representing a sensitive and non-invasive method of early diagnosis of PDAC. In this review, we will discuss the advantages and pitfalls of cfDNA methylation studies. Further, we will present the current advances in the discovery of pancreatic cancer biomarkers with early diagnostic or prognostic potential, focusing on pancreas-specific (e.g., CUX2 or REG1A) or abnormal (e.g., ADAMTS1 or BNC1) cfDNA methylation signatures in high risk pre-neoplastic conditions and PDAC.

SUBMITTER: Brancaccio M

PROVIDER: S-EPMC7017422 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers' Discovery.

Brancaccio Mariarita M Natale Francesco F Falco Geppino G Angrisano Tiziana T

Genes 20191223 1

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancer types world-wide. Its high mortality is related to the difficulty in the diagnosis, which often occurs when the disease is already advanced. As of today, no early diagnostic tests are available, while only a limited number of prognostic tests have reached clinical practice. The main reason is the lack of reliable biomarkers that are able to capture the early development or the progression of the disease. Hence, the discovery ...[more]

PMID: 31877923

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Project description:Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is growing in incidence but treatment options remain limited, particularly for late stage disease. As liver cirrhosis is the principal risk state for HCC development, markers to detect early HCC within this patient population are urgently needed. Perturbation of epigenetic marks, such as DNA methylation (5mC), is a hallmark of human cancers, including HCC. Identification of regions with consistently altered 5mC levels in circulating cell free DNA (cfDNA) during progression from cirrhosis to HCC could therefore serve as markers for development of minimally-invasive screens of early HCC diagnosis and surveillance. Methods: To discover DNA methylation derived biomarkers of HCC in the background of liver cirrhosis, we profiled genome-wide 5mC landscapes in patient cfDNA using the Infinium HumanMethylation450k BeadChip Array. We further linked these findings to primary tissue data available from TCGA and other public sources. Using biological and statistical frameworks, we selected CpGs that robustly differentiated cirrhosis from HCC in primary tissue and cfDNA followed by validation in an additional independent cohort. Results: We identified CpGs that segregate patients with cirrhosis, from patients with HCC within a cirrhotic liver background, through genome-wide analysis of cfDNA 5mC landscapes. Lasso regression analysis pinpointed a panel of probes in our discovery cohort that were validated in two independent datasets. A panel of five CpGs (cg04645914, cg06215569, cg23663760, cg13781744, and cg07610777) yielded area under the receiver operating characteristic (AUROC) curves of 0.9525, 0.9714, and 0.9528 in cfDNA discovery and tissue validation cohorts 1 and 2, respectively. Validation of a 5-marker panel created from combining hypermethylated and hypomethylated CpGs in an independent cfDNA set by bisulfite pyrosequencing yielded an AUROC of 0.956, compared to the discovery AUROC of 0.996. Conclusion: Our finding that 5mC markers derived from primary tissue did not perform well in cfDNA, compared to those identified directly from cfDNA, reveals potential advantages of starting with cfDNA to discover high performing markers for liquid biopsy development.

Project description:Background:Colorectal cancer is the fourth cause of cancer-related deaths worldwide, though detection at early stages associates with good prognosis. Thus, there is a clear demand for novel non-invasive tests for the early detection of colorectal cancer and premalignant advanced adenomas, to be used in population-wide screening programs. Aberrant DNA methylation detected in liquid biopsies, such as serum circulating cell-free DNA (cfDNA), is a promising source of non-invasive biomarkers. This study aimed to assess the feasibility of using cfDNA pooled samples to identify potential serum methylation biomarkers for the detection of advanced colorectal neoplasia (colorectal cancer or advanced adenomas) using microarray-based technology. Results:cfDNA was extracted from serum samples from 20 individuals with no colorectal findings, 20 patients with advanced adenomas, and 20 patients with colorectal cancer (stages I and II). Two pooled samples were prepared for each pathological group using equal amounts of cfDNA from 10 individuals, sex-, age-, and recruitment hospital-matched. We measured the methylation levels of 866,836 CpG positions across the genome using the MethylationEPIC array. Pooled serum cfDNA methylation data meets the quality requirements. The proportion of detected CpG in all pools (> 99% with detection p value < 0.01) exceeded Illumina Infinium methylation data quality metrics of the number of sites detected. The differential methylation analysis revealed 1384 CpG sites (5% false discovery rate) with at least 10% difference in the methylation level between no colorectal findings controls and advanced neoplasia, the majority of which were hypomethylated. Unsupervised clustering showed that cfDNA methylation patterns can distinguish advanced neoplasia from healthy controls, as well as separate tumor tissue from healthy mucosa in an independent dataset. We also observed that advanced adenomas and stage I/II colorectal cancer methylation profiles, grouped as advanced neoplasia, are largely homogenous and clustered close together. Conclusions:This preliminary study shows the viability of microarray-based methylation biomarker discovery using pooled serum cfDNA samples as an alternative approach to tissue specimens. Our strategy sets an open door for deciphering new non-invasive biomarkers not only for colorectal cancer detection, but also for other types of cancers.

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Dataset Information

Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers' Discovery.

Publications

Cell-Free DNA Methylation: The New Frontiers of Pancreatic Cancer Biomarkers' Discovery.

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