Abstract
PurposeThe present study was conducted to clarify the clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma (PDAC).MethodsGenome-wide DNA methylation screening was performed using the Infinium HumanMethylation450 BeadChip, and DNA methylation quantification was verified using pyrosequencing. We analyzed fresh-frozen tissues from an initial cohort (17 samples of normal control pancreatic tissue [C] from 17 patients without PDAC, and 34 samples of non-cancerous pancreatic tissue [N] and 82 samples of cancerous tissue [T] both obtained from 82 PDAC patients) and formalin-fixed paraffin-embedded T samples from 34 patients in a validation cohort.ResultsThe DNA methylation profiles of N samples tended to differ from those of C samples, and 91,907 probes showed significant differences in DNA methylation levels between C and T samples. Epigenetic clustering of T samples was significantly correlated with a larger tumor diameter and early recurrence (ER), defined as relapse within 6 months after surgery. Three marker CpG sites, applicable to formalin-fixed paraffin-embedded surgically resected materials regardless of their tumor cell content, were identified for prediction of ER. The sensitivity and specificity for detection of patients belonging to the ER group using a panel combining these three marker CpG sites, including a CpG site in the CDK14 gene, were 81.8% and 71.7% and 88.9% and 70.4% in the initial and validation cohorts, respectively.ConclusionThese findings indicate that DNA methylation alterations may have a clinicopathological impact on PDAC. Application of our criteria will ultimately allow prediction of ER after surgery to improve the outcome of PDAC patients.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has become one of the major causes of cancerrelated death in the United States (Siegel et al 2016) and Japan (Egawa et al 2012)
The Infinium assay identified 91,907 probes that were aberrantly methylated in the 82 T samples of the initial cohort (P value < 0.05 by Welch’s t test with Bonferroni correction and ΔβT-C value > 0.1 or < − 0.1) compared to the 17 C samples, indicating that DNA methylation alterations had occurred in T samples and participate in pancreatic carcinogenesis
Based on the present principal component analysis (PCA) by Infinium assay, the DNA methylation profile of N samples, which were obtained from patients with PDAC and may already have been exposed to carcinogenetic factors, tended to differ from that of C samples (Fig. 1a)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has become one of the major causes of cancerrelated death in the United States (Siegel et al 2016) and Japan (Egawa et al 2012). Previous studies have suggested that tumor size, carbohydrate antigen 19-9 (CA19-9), histologic type, lymph-node metastasis, and microvascular or perineurial invasion are predictive factors for recurrence of PDAC after surgery (Groot et al 2019; Kurahara et al 2018; Matsumoto et al 2015; Nishio et al 2017; Sugiura et al 2012). Such factors alone are not yet sufficiently predictive of ER, and an extensive search for molecular-based biomarkers of ER risk in PDAC is warranted
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