Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases

Abstract

The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases. Background: Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver. Methods: A total of 87 small primary PanNETs (<3cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization.

The evolving (epi)genetic landscape of pancreatic neuroendocrine tumours

“…Therefore, menin/MEN1 alterations are considered as early events in the pathogenesis of PanNETs (de Wilde et al 2012b, Hackeng et al 2016. ATRX/DAXX loss/mutations and ALT positivity have been associated with larger tumours (>2-3 cm, G2, T3/T4), chromosomal instability, metastatic disease and reduced relapse-free and tumourspecific survival (Marinoni et al 2014, Pea et al 2018 suggesting that these changes are a later event in tumour evolution. This established association may, therefore, have a potential value as a marker of aggressiveness for patient stratification.…”

“…Of note, ALT status was not tested in either multivariate analyses. However, a recent study identified ALT positivity through multivariate analysis as an independent risk factor for liver metastases (Pea et al 2018).…”

“…3. Losses are more frequently detected in non-metastatic tumours, while gains in metastatic disease (Pea et al 2018). 4.…”

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

“…In addition to driver mutations affecting individual genes, copy number aberrations (CNA) have been used to characterize these tumors 16,[24][25][26] . Recent work has revealed four distinct subtypes based on chromosome arm length CNA patterns: i) recurring copy number losses of specific chromosomes, ii) limited copy number events with mostly loss of chromosome 11, iii) polyploidy tumors and iv) aneuploidy tumors 16 .…”

“…In addition, the first two groups harbor MEN1 mutations in combination with loss of chromosome 11, resulting in a bi-allelic inactivation of this tumor suppressor gene 24 . The aneuploid tumors also show frequent DAXX/ATRX loss of expression along with an alternative telomerase lengthening phenotype 25 .…”