The landscape of molecular alterations in pancreatic and small intestinal neuroendocrine tumours

Abstract Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) arise throughout the gut and feature varying biological behaviour and malignant potential. GEP-NENs include two genetically different entities, well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NEC). NECs are characterized by a dismal prognosis and by distinctive TP53 and RB1 inactivation which sets them apart from NETs. The latter, conversely, have a wide spectrum of aggressiveness and molecular alterations. Knowledge on their biology has recently expanded thanks to high-throughput studies focused on two important groups of well-differentiated neuroendocrine neoplasms: pancreatic (PanNETs) and small intestinal (SiNETs) tumours. PanNETs have been among the most studied also due to genetic syndromes featuring their onset. Research stemming from this observation has uncovered the inactivation of MEN1 , VHL , TSC1/2 , and the hyperactivation of the PI3K/mTOR pathway as distinctive biological features of these neoplasms. Next-Generation Sequencing added information on the role of telomere lengthening via ATRX/DAXX inactivation in a fraction of PanNETs, while other display shortened telomeres and recurrent chromosomal alterations. The data so far disclosed a heterogeneous combination of driver events, yet converging into four pathways including DNA damage repair, cell cycle regulation, PI3K/mTOR signalling and telomere maintenance. SiNETs showed a lesser relationship with mutational driver events, even in the case of familial cases. High throughput studies identified putative driver mutations in CDKN1 and APC which, however, were reported in a minor fraction (∼10%) of cases. Tumorigenesis of SiNETs seems to depend more on chromosomal alterations (loss of chromosome 8, gains at 4, 5 and 20) and epigenetic events, which converge to hyperactivate the PI3K/mTOR, MAPK and Wnt pathways. While calling for further integrative studies, these data lay previous and recent findings in a more defined frame and provide clinical research with several candidate markers for patient stratification and companion diagnostics.