1. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup.
- Author
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Chan CS, Laddha SV, Lewis PW, Koletsky MS, Robzyk K, Da Silva E, Torres PJ, Untch BR, Li J, Bose P, Chan TA, Klimstra DS, Allis CD, and Tang LH
- Subjects
- Co-Repressor Proteins, DNA Methylation genetics, DNA Methylation physiology, Humans, Immunohistochemistry, Molecular Chaperones, Promoter Regions, Genetic genetics, Prospective Studies, Retrospective Studies, Adaptor Proteins, Signal Transducing genetics, Neuroendocrine Tumors genetics, Nuclear Proteins genetics, Proto-Oncogene Proteins genetics, X-linked Nuclear Protein genetics
- 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.
- Published
- 2018
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