Clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma: prediction of early recurrence based on genome-wide DNA methylation profiling

J Cancer Res Clin Oncol. 2021 May;147(5):1341-1354. doi: 10.1007/s00432-021-03541-6. Epub 2021 Feb 26.

Abstract

Purpose: The present study was conducted to clarify the clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma (PDAC).

Methods: Genome-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.

Results: The 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.

Conclusion: These 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.

Keywords: DNA methylation; Ductal adenocarcinoma; Early recurrence; Infinium assay; Pancreas.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cohort Studies
  • CpG Islands / genetics
  • Cyclin-Dependent Kinases / genetics
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics
  • Female
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology*
  • Paraffin Embedding / methods
  • Tissue Fixation / methods

Substances

  • Biomarkers, Tumor
  • Cyclin-Dependent Kinases

Supplementary concepts

  • Pancreatic Carcinoma