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

<jats:title>Abstract</jats:title><jats:p>The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are <jats:italic>ATRX</jats:italic>, <jats:italic>DAXX</jats:italic>, and <jats:italic>MEN1</jats:italic>. We genotyped 64 PanNETs and found 58% carry <jats:italic>ATRX</jats:italic>, <jats:italic>DAXX</jats:italic>, and <jats:italic>MEN1</jats:italic> 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 <jats:italic>ARX</jats:italic> and low <jats:italic>PDX1</jats:italic> gene expression with <jats:italic>PDX1</jats:italic> 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 <jats:italic>q</jats:italic>-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.</jats:p>