ATRX, DAXX or MEN1mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup

Abstract

The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs)

Pancreatic Neuroendocrine Neoplasms: Landscape and Horizon

“…19 Patients with PanNEC have rapid clinical progression and require prompt cytotoxic chemotherapy, usually with platinum-based regimens, and they are likely to have a transient but refractory response, particularly those with small cell carcinomas. 21 Genomic investigation has established that more than 40% of PanNETs have DAXX/ATRX and MEN1 gene mutations 22,23 ; but these mutations are not identified in pancreatic NECs. In contrast, commonly mutated genes in pancreatic ductal adenocarcinomas (TP53, SMAD4, KRAS) are frequently seen in PanNECs with additional RB gene mutations, which are extremely rare in PanNETs.…”

“…Advances in nextgeneration sequencing technology have enabled genomewide analyses of PanNETs, which have highlighted the molecular heterogeneity of the disease. 22,23,35 Many of the genes targeted in the development of pancreatic ductal adenocarcinoma (including PanNEC and combined adenocarcinoma and PanNEC) are not present in PanNETs. In particular, KRAS, TP53, p16/cdkn2A, and SMAD4 are not mutated in most PanNETs.…”

“…Thus, collectively about 60% of PanNETs carry MEN1/DAXX/ATRX mutations. 23,28 Since these genes affect the epigenetic landscape, the epigenome including DNA methylation, histone modification, posttranscriptional regulation, and ultimately gene expression likely plays a critical role in the pathogenesis of PanNET. 28 While the precise molecular mechanisms associated with these gene mutations remain to be further delineated, PanNETs with MEN1/ DAXX/ATRX mutant genotype as a group correlate with a worse clinical prognosis than tumors carrying the wild-type alleles of MEN1/DAXX/ATRX.…”

“…28 While the precise molecular mechanisms associated with these gene mutations remain to be further delineated, PanNETs with MEN1/ DAXX/ATRX mutant genotype as a group correlate with a worse clinical prognosis than tumors carrying the wild-type alleles of MEN1/DAXX/ATRX. 23 From their differential gene expression profiles, MEN1/DAXX/ATRX-mutant PanNETs exhibit gene signatures of islet a-cell lineage of the pancreas, while MEN1/DAXX/ATRX wild-type PanNETs are more heterogenous in gene expressions. 23 These findings suggest that while PanNETs may seemingly present as a single clinical disease, they can be further characterized into different subtypes on the basis of their cell lineage and the associated molecular genotype.…”

“…23 From their differential gene expression profiles, MEN1/DAXX/ATRX-mutant PanNETs exhibit gene signatures of islet a-cell lineage of the pancreas, while MEN1/DAXX/ATRX wild-type PanNETs are more heterogenous in gene expressions. 23 These findings suggest that while PanNETs may seemingly present as a single clinical disease, they can be further characterized into different subtypes on the basis of their cell lineage and the associated molecular genotype. Understanding the epigenetic and transcriptional dysregulation of PanNETs will require comparison to their proper cells of origin, which may explain the unpredictable outcome of the disease and facilitate the development of unique and targeted therapeutic strategies.…”