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

Mariarita Brancaccio,Tiziana Angrisano,Francesco Natale,Geppino Falco

doi:10.3390/genes11010014

Mariarita Brancaccio, Tiziana Angrisano + Show 2 more

Open Access

https://doi.org/10.3390/genes11010014

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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.

Highlights

chronic pancreatitis (CP) is a long-lasting inflammation of the pancreas that alters the normal structure and function of the organ, and it represents one of the major risk factors for the development of Pancreatic ductal adenocarcinoma (PDAC) [1]
Li and colleagues analyzed cell-free DNA (cfDNA) 5hmC profiles in patients diagnosed with colorectal, gastric, liver, thyroid, or pancreatic cancer, using genomic DNA of paired tumors or adjacent tissues as the comparator [53]
Disease, with a combined sensitivity of 97.3% and specificity of 91.6%. These results are encouraging, indicating that the combined cfDNA methylation status of ADAMTS1 and BNC1 is a powerful tool for detecting pancreatic cancer during the early stages (i.e., I and II) when curative resection of the tumor is still possible

Summary

Introduction

CP is a long-lasting inflammation of the pancreas that alters the normal structure and function of the organ, and it represents one of the major risk factors for the development of PDAC [1]. Changes in DNA methylation often occur at early stages of tumorigenesis [15] This has been confirmed for bladder [16], breast [17], colorectal [18], and lung cancers [19,20], as well as for pre-neoplastic lesions of the pancreas [21,22,23,24]. Exploiting the relation between abnormally methylated cfDNA and pre-neoplastic lesions of the pancreas or CP may become a game changing approach for the development of PDAC-specific diagnostic or prognostic tools. We will describe abnormal cfDNA methylation signatures in high risk pre-neoplastic conditions and PDAC and present the current advances in pancreatic cancer diagnostic and prognostic biomarker discovery.

Pitfalls in cfDNA Data Interpretation

Method

Findings

Discussion and Conclusions