Endocrine Abstracts

Pancreatic neuroendocrine tumours (PanNETs) are clinically challenging diseases as they display variable outcomes. We performed genome sequencing on 100 sporadic, primary pancreatic neuroendocrine tumours (PanNETs) and defined the underlying mutagenic mechanisms and mutations promoting this rare malignancy. Genome-wide analysis showed PanNETs to have a lower mutation burden and greater genomic stability than pancreatic exocrine cancers. The most common mutational signatures were Deamination, APOBEC, and the unknown aetiology signature five of Alexandrov et al. (Nature, 2013). In addition, 6/100 patients had a novel mutational signature. A single PanNET had a BRCA-deficient mutational signature due to a BRCA2 homozygous deletion. Chromothripsis occurs rarely and involves chromosome 11q inactivating MEN1 gene. Alternative Lengthening of Telomere (ALT) was detected in 60% of cases and these were heavily enriched for DAXX and ATRX mutations. Driver gene analysis confirmed pathogenic mutations in MEN1 (42% mutated, 3% homozygously deleted, 5% damaged by SV), ALT promoting mutations in DAXX (24%) and ATRX (11%), recurrent mutations mTOR signalling components (20%). CNV analysis found three major molecular tumour classes confirming previous published suggestions. Integrated mRNA and miRNA profiling of human PanNETs identifies three distinct subtypes classified into insulin-like (IT), metastasis-like (MLP), and MEN1-like. MLP tumors express pancreas development genes, whereas IT tumors express mature islet cell genes.