Abstract
The clinical outcomes of pancreatic ductal adenocarcinoma (PDAC) remain dismal, with an estimated five-year survival rate of less than 5%. Early detection and prognostic approaches, including robust biomarkers for PDAC, are critical for improving patient survival. Our goal was to explore the biomarker potential of 5-hydroxymethylcytosines (5hmC), an emerging epigenetic marker with a distinct role in cancer pathobiology, yet under-investigated, due largely to technical constraints relating to PDAC. The TET-assisted bisulfite (TAB)-Array assay represents state-of-the-art technology and was used to directly profile 5hmC at single-base resolution with the Illumina EPIC array (~850,000 cytosine modification sites) in 17 pairs of tumor/adjacent tissue samples from US patients collected at the University of Chicago Medical Center. The TAB-Array data were analyzed to explore the genomic distribution of 5hmC and evaluate whether 5hmC markers were differentially modified between tumors and adjacent tissues. We demonstrated distinctive distribution patterns of 5hmC in tissue samples from PDAC patients relative to cis-regulatory elements (e.g., histone modification marks for enhancers), indicating their potential gene regulatory relevance. Substantial differences in 5hmC-modified CpG sites were detected between tumors and adjacent tissues in genes related to cancer pathobiology. The detected 5hmC-contaning marker genes also showed prognostic value for overall survival in the US patients with PDAC from the Cancer Genome Atlas Project. This study demonstrated the technical feasibility of the TAB-Array approach in cancer biomarker discovery and the biomarker potential of 5hmC for PDAC. Future studies using tissues and/or liquid biopsies may include 5hmC as a potential epigenetic biomarker target for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) ranks fourth in the United States and eighth worldwide for cancer mortality, with an estimated five-year survival rate of only 5%, in part because it is usually detected at the stage when it is no longer surgically resectable [1]
5-hydroxymethylcytosines (5hmC)—which are epigenetic marks that can be generated by oxidation of the more common 5-methylcytosines (5mC) through the TET family of enzymes—have emerged as a stable type of modified cytosine in the human genome, covering ~0.1–1%
Consistent with previous epigenetic studies using the Infinium arrays [14,16], the detected 5mC in PDAC tissues showed a two-mode distribution with peaks at both the lower and upper end of modification levels (0.8 in terms of β-value)
Summary
Pancreatic ductal adenocarcinoma (PDAC) ranks fourth in the United States and eighth worldwide for cancer mortality, with an estimated five-year survival rate of only 5%, in part because it is usually detected at the stage when it is no longer surgically resectable [1]. Reliable early detection and prevention is the only viable option for increased chances of survival but is currently unavailable. The cancer biomarkers that are currently clinically available for PDAC, such as carbohydrate antigen (CA) 19-9, do not show satisfactory sensitivity and specificity for clinical utility [3]. The identification of more effective biomarker targets for early detection, diagnosis, prognosis, and precise management of this fatal disease remains a great challenge. Though the rapid advancement of high-throughput sequencing technologies has allowed for the characterization of tumor-related mutations, the low mutation frequency and lack of information on tissue of origin hampers detection sensitivity and specificity based on mutations alone. Recent studies have demonstrated aberrant cytosine modifications in tumors, suggesting potential applications of these epigenetic markers in cancer early detection and diagnosis [4,5]. 5-hydroxymethylcytosines (5hmC)—which are epigenetic marks that can be generated by oxidation of the more common 5-methylcytosines (5mC) through the TET (ten-eleven translocation) family of enzymes—have emerged as a stable type of modified cytosine in the human genome, covering ~0.1–1%
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