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- Title
Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors.
- Authors
Tirosh, Amit; Mukherjee, Sanjit; Lack, Justin; Gara, Sudheer Kumar; Wang, Sophie; Quezado, Martha M.; Keutgen, Xavier M.; Wu, Xiaolin; Cam, Maggie; Kumar, Suresh; Patel, Dhaval; Nilubol, Naris; Tyagi, Monica Varun; Kebebew, Electron
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
NEUROENDOCRINE tumors; VON Hippel-Lindau disease; METHYLATION; ISLANDS of Langerhans; PANCREATIC tumors; MULTIPLE tumors; GENE expression
- Publication
Cancer (0008543X), 2019, Vol 125, Issue 8, p1247
- ISSN
0008-543X
- Publication type
journal article
- DOI
10.1002/cncr.31930