Molecular characterization of Pancreatic NeuroEndocrine Tumors (PanNETs)

Purpose: To identify clinically relevant molecular alterations associated to pancreatic endocrine tumors (PanNETs) discovered by recent exome sequencing data. Patients and Methods: A series of 204 PanNETs were explored for intragenic mutations in 8 genes reported as recurrently altered in PanNETs using Ion Torrent technology. The 8 genes were MEN1, ATM, ATRX, DAXX, PIK3CA, TSC2, PTEN, MTOR. Their relation with chromosomal copy number aberrations were assessed in 90 cases having CGH array data available, and in a selected number of cases alternative lengthening of telomeres (ALT) was investigated by FISH. A total of 171 PanNETs were also investigated by immunohistochemistry for Menin, Atrx, Daxx, Atm and Pten. Results: Our targetted next-generation mutational analysis of 204 PanNETs for three chromatin remodelling genes (MEN1, ATRX, DAXX), MTOR pathway genes (PTEN, TSC2, PIK3CA, MTOR) and the ATM DNA repair gene assessed that 112/204 (55%) PanNETS had mutations, while 92 (45%) lacked mutations, and: i) the mutually exclusive mutations in DAXX and ATRX chromatin remodelling genes were the most frequent, accounting for 53/204 (26%) cases, and were associated with MEN1 or ATM mutations that were in turn mutually exclusive; ii) DAXX/ATRX mutations are associated with a subset of PanNETS showing a peculiar pattern of recurrent chromosomal losses; iii) the mutually exclusive mutations in genes belonging to mTOR pathways were found in 31/204 (15%), and mTOR pathway activation is associated with shorter disease-free survival. Conclusions: We report that PanNET can be subdived into two main molecular subgroups. The first showing the peculiar simultaneous loss of twelve chromosomes, which includes the vast majority of neoplasms showing MEN1 mutations and concurrent mutations in DAXX, ATRX, PTEN and TSC2. The second group, where only a small number of cases shows MEN1 mutations, lacks recurrent chromosomal anomalies and the gene alterations responsible for their development remain to be discovered.