Next generation exome sequencing of Pancreatic Neuroendocrine Neoplasms (PanNENs)

Purpose: To identify clinically relevant molecular alterations associated to pancreatic endocrine neoplasms (PanNENs). Patients and Methods: Exome sequencing and chromosomal copy number aberrations were investigated on a discovery set of 37 PanNENs. Exome sequencing data were validated in 128 PanNENs using Ion Torrent technology. A series of 90 samples were also analyzed by SNP arrays to investigate the presence of chromosome copy number alterations. A series of 171 PanNENs was further investigated by immunohistochemistry for Menin and Atm. Results: Recurrent mutations implicating a number of known and previously unidentified genes included ARID1A (2.5%), ATM (5.5%), ATRX (12%), DAXX (20%), MEN1 (35%), PTEN (8%), TSC2 (5.5%), and TAF1 (3.8%). ATRX, DAXX and PTEN mutations clustered in a group of samples (50%) showing a set of recurrent chromosome losses (RCL) in chromosomes 1,2,3,6,8,10,11,15, 16,18,21,22 and X. The RCL group showed an increased (+59%) overall mutation rate, correlated with the presence of MEN1 mutations (P < 0.001) and presence of distant metastasis (P = 0.001). Conclusions: We describe for the first time a subclass of PanNENs in which the mutations in MEN1 gene identify a subclass distinguished by the presence of a highly consistent pattern of recurrent chromosome losses. Patients within this class show a better prognosis when compared with patients with similar clinical conditions without the RCL features.