ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup Journal Article


Authors: Chan, C. S.; Laddha, S. V.; Lewis, P. W.; Koletsky, M. S.; Robzyk, K.; Da Silva, E.; Torres, P. J.; Untch, B. R.; Li, J.; Bose, P.; Chan, T. A.; Klimstra, D. S.; Allis, C. D.; Tang, L. H.
Article Title: ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup
Abstract: The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. We genotyped 64 PanNETs and found 58% carry ATRX, DAXX, and MEN1 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 high ARX and low PDX1 gene expression with PDX1 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 (FDR q-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. © 2018, The Author(s).
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-10-12
Start Page: 4158
Language: English
DOI: 10.1038/s41467-018-06498-2
PUBMED: 30315258
PROVIDER: scopus
PMCID: PMC6185985
DOI/URL:
Notes: Article -- Export Date: 1 November 2018 -- Source: Scopus
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MSK Authors
  1. Timothy Chan
    206 Chan
  2. David S Klimstra
    832 Klimstra
  3. Laura Hong Tang
    308 Tang
  4. Kenneth Robzyk
    5 Robzyk
  5. Brian Untch
    23 Untch
  6. Janet Wing Yui Li
    5 Li
  7. Promita   Bose
    7 Bose