Molecular Genetics of Pancreatic Endocrine Tumours

Abstract

Pancreatic tumours with neuroendocrine phenotype comprise 1–2% of all pancreatic tumours and commonly occur in a sporadic setting. Up to 10% of pancreatic neuroendocrine tumours (PNETs) may occur as part of inherited tumour‐predisposing syndromes, including multiple endocrine neoplasia type 1, von Hippel–Lindau disease, neurofibromatosis type 1, tuberous sclerosis complex and glucagon cell adenomatosis. Recent advances in genetics and pathology have allowed better understanding of the role of genetic abnormalities that underlie hereditary and sporadic PNETs. Ongoing research in this fast‐changing field has led to the discovery of mutations in key genes that determine how tumours begin, evolve and behave. Major specific tumour pathways of PNETs involve abnormalities of MEN1 , DAXX / ATRX , and mammalian target of rapamycin ( mTOR ) pathway genes ( PTEN , TSC2, and PIK3CA ). New knowledge in the field of genetics of PNETs potentially permits development of effective diagnostic methods and targeted therapies aimed at improving prognosis and disease‐free survival rates. Key Concepts Hereditary and sporadic pancreatic neuroendocrine tumours (PNETs) demonstrate characteristic histo‐morphology and genetics that determine biology, treatment response and prognosis. Tumour‐predisposing syndromes with increased risk of developing PNETs include multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau disease (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC). Recent advances in the pathology and genetics of PNETs have unraveled the role of genetic abnormalities in tumour pathways that may lead to better diagnostic and therapeutic paradigms. Major specific tumour pathways of PNETs involve abnormalities of MEN1 , DAXX / ATRX , and mammalian target of rapamycin ( mTOR ) pathway genes ( PTEN , TSC2, and PIK3CA ).