ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Chan, Chang; Laddha, Saurabh; Lewis, Peter; Koletsky, Matthew; Robzyk, Kenneth; Silva, Edaise; Torres, Paula; Untch, Brian; Li, Janet; Bose, Promita; Chan, Timothy; Klimstra, David; Allis, C.; Tang, Laura
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 10
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06498-2
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) areATRX, DAXX, andMEN1 . We genotyped 64 PanNETs and found 58% carryATRX, DAXX, andMEN1 mutations (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis to reveal two distinct subgroups with one consisting entirely of A-D-M mutant PanNETs. Two genes differentiating A-D-M mutant from A-D-M WT PanNETs were highARX and lowPDX1 gene expression withPDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha-cells (FDRq -value < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells. In pancreatic neuroendocrine tumors (PanNETs) ATRX, DAXX, and MEN1 are commonly mutated (A-D-M mutant PanNETs). Here, the authors find in a cohort of PanNETS 58% are A-D-M mutant PanNETs, with a worse clinical outcome and differences in gene expression and methylation compared to A-D-M wild type cases- these gene expression differences suggest that A-D-M mutant PanNETs potentially originate from a cell type similar to alpha cells.