Methylation Heterogeneity within Human non-functional Pancreatic neuroendocrine tumors (PanNETs). Methylation Heterogeneity within Human non-functional Pancreatic neuroendocrine tumors (PanNETs)

DNA CpG methylation profiling of PanNETs patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (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 on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression 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 (pval < 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. Overall design: 32 PanNETs tumor specimens were obtained from MKSCC and samples were probed for DNA CpG methylation using Illumina Methylation 450K array and processed as per manufacturers instructions