Inherited and Somatic Genetics of Pancreatic Neuroendocrine Tumors

Abstract

Pancreatic neuroendocrine tumors (PNETs) are rare tumors, categorized as functional and nonfunctional tumors based on whether they can retain the ability to release hormones such as insulin, gastrin, or glucagon and they follow the classic model of tumor progression. Eighty-five percent of PNETs are nonfunctional; they are associated with a worse prognosis compared to functional PNETs, likely secondary to diagnosis at later stages. The five-year survival rate for metastatic nonfunctional PNETs is only 30–40 %. This poor prognosis for patients with metastatic or regional disease underscores the urgent need for more effective therapies. Although most PNETs are sporadic, some are associated with cancer predisposition syndromes including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel–Lindau disease (vHL), and more rarely with Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC). Somatic mutations in PNETs are commonly seen in MEN1 (44 %) and a study using massively parallel sequencing also identified common somatic mutations in a chromatin remodeling complex involving two genes, ATRX and DAXX (18 % and 25 %, respectively), and in the mTOR pathway in two genes, TSC2 (8.8 %) and PTEN (7.3 %). Although a complete understanding of the tumor biology and somatic genetics is lacking, the identification of these new somatic mutations may serve as potential prognostic markers or even targets for therapeutic intervention.