Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors

Cancer. 2019 Apr 15;125(8):1247-1257. doi: 10.1002/cncr.31930. Epub 2019 Jan 8.


Background: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs.

Methods: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools.

Results: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs.

Conclusions: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.

Keywords: DNA methylation; multiple endocrine neoplasia type 1 (MEN1); nonfunctioning; pancreatic neuroendocrine tumor; von Hippel-Lindau (VHL).

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Carcinoma, Neuroendocrine / classification*
  • Carcinoma, Neuroendocrine / genetics
  • CpG Islands
  • DNA Methylation*
  • Down-Regulation
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Pancreatic Neoplasms / classification*
  • Pancreatic Neoplasms / genetics
  • Proto-Oncogene Proteins / genetics
  • RNA-Binding Proteins / genetics*
  • Repressor Proteins / genetics*
  • Unsupervised Machine Learning
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Whole Genome Sequencing / methods*


  • Adaptor Proteins, Signal Transducing
  • CDCA7L protein, human
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • RBM47 protein, human
  • RNA-Binding Proteins
  • Repressor Proteins
  • SFRP5 protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human