Landscape of genomic alteration of Pancreatic Neuroendocrine Tumours

Pancreatic Neuroendocrine Tumors (PanNETs) are rare malignancies with a wide range of clinical-pathological characteristics and different prognosis with a challenging clinical management. They typically carry out modifications of tumour suppressor pathways and no oncogenic alterations have been found yet. The recent acquisitions on the biological behavior of these rare tumors, due to the analysis of large cohorts of patients with consistent follow up data, lead to a change in classification of PanNETs in recent years. Our group recently identified novel pathways (mTOR, chromatin-remodeling and DNA repair) involved in PanNETs tumorigenesis, demonstrating that 60% of PanNETs had mutations in one of the genes involved in these pathways. We performed whole genome sequencing of 102 primary G1-G2 PanNETs in order to dissect the genomic events that underpin their pathogenesis. Mutations in DAXX/ATRX, mTOR pathway and alterations in the regulation of telomere length mechanism resulted correlated to worse survival. We describe 5 mutational signatures, including a novel G:C>T:A Base-Excision-Repair-deficiency signature due to MUTYH inactivation. We uncover a larger than expected proportion of germline mutations in clinically sporadic PanNETs. These include previously unreported mutations in DNA repair genes MUTYH, CHEK2, and BRCA2, which together with MEN1 and VHL occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, commonly occurred in genes involved in 4 main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling, (including novel EWSR1 gene fusions), and telomere maintenance. Copy number analysis performed by SNP-array, identified 4 distinct groups characterized by different patterns of chromosomal losses and gains. The group identified by the presence of recurrent chromosomal losses, with recurrent loss of chromosome 11, where resides MEN1 locus, resulted enriched for DAXX/ATRX mutations and altered telomere length. In addition, gene expression analyses identified a subgroup of PanNETs associated with upregulation of hypoxia and HIF signalling. These results open novel scenario on the understanding of PanNETs biology and uncover potential prognostic biomarkers able to better predict and stratify the prognosis of patients and influence their clinical management.