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

Chang S Chan,David S Klimstra,Paula J Torres,Laura H Tang,Matthew S Koletsky,Peter W Lewis,Kenneth Robzyk,Saurabh V Laddha,Timothy A Chan,Brian R Untch,Janet Li,Edaise Da Silva,Promita Bose,C David Allis

doi:10.1038/s41467-018-06498-2

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.

Highlights

The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1
While well-differentiated PanNETs can be successfully treated with surgery, there are few treatments for metastatic PanNETs, and they do not respond to conventional chemotherapy
Molecular studies have identified mutations in MEN1, ATRX, and DAXX to be the most commonly found in PanNETs5,6

Summary

Introduction

The commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Knowledge of functional PanNETs has evolved from insulinoma to almost a dozen other diverse hormone-secreting tumors These individual lesions may have specific clinical, pathologic, and genetic associations, including multiple endocrine neoplasia type 1 (MEN-1), tuberous sclerosis, and von Hippel-Lindau (VHL) syndromes. Molecular studies have identified mutations in MEN1, ATRX, and DAXX to be the most commonly found in PanNETs5,6 (found in approximately 40, 10, and 20% of tumors, respectively). We genotyped 64 well differentiated PanNETs for mutations in ATRX, DAXX, and MEN1 and performed RNA sequencing (n = 33) and DNA methylation (n = 32) analysis to identify distinct molecular phenotypes of A-D-M mutant PanNETs which potentially reveals their distinct cell of origin or transdifferentiated state

Methods

Results

Conclusion