Genetics of pancreatic neuroendocrine tumors: implications for the clinic

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated.

Keywords:

• genetics
• islet cell tumor
• mutation
• pancreatic neuroendocrine tumor
• PanNET
• sequencing

Financial & competing interests disclosure

The authors were supported by a grant from the National Institute of Health (NIH grant CA62924) and a grant from the Italian Foundation for the Research on Pancreatic Diseases (FIMP). L.D. Wood works as a consultant for Personal Genome Diagnostics. R.H. Hruban receives royalty payments from Myriad Genetics for the PALB2 invention. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and are clinically and biologically distinct from pancreatic ductal adenocarcinoma.

• PanNETs are a feature of many familial cancer syndromes. They occur commonly in patients with multiple endocrine neoplasia type 1 and von Hippel–Lindau disease, while they are uncommon in patients with neurofibromatosis type 1 and tuberous sclerosis complex.

• Recent high-throughput sequencing studies of sporadic (non-familial) PanNETs have identified many of the key genetic drivers in this tumor type.

• The MEN1 tumor suppressor gene is somatically mutated in almost half of sporadic PanNETs. This gene likely plays a role in the early steps of PanNET tumorigenesis. Some studies have suggested that patients with somatic mutations in MEN1 have an improved prognosis, but data on this are inconsistent.

• Mutations in the genes ATRX and DAXX occur in almost half of sporadic PanNETs. Loss of ATRX or DAXX expression (a surrogate for mutation) is associated with the alternative lengthening of telomeres phenotype, a telomerase-independent mechanism of telomere maintenance. Similar to MEN1, the data on the relationship between ATRX and DAXX mutations and prognosis are inconsistent.

• Approximately 15% of PanNETs have somatic mutations in genes that encode components of the mTOR pathway, including TSC2, PIK3CA and PTEN. These mutations highlight the importance of the mTOR pathway in PanNET tumorigenesis, and this pathway can be therapeutically targeted by drugs, such as everolimus.

• PanNETs are graded based on proliferation rate, with the highest grade designated as neuroendocrine carcinomas. However, this group is heterogeneous, containing both PanNETs with an elevated proliferation rate and cytologically malignant neuroendocrine carcinomas. These two groups are genetically distinct, with TP53 and RB mutations in the latter group.

• Surgery is a mainstay of treatment of PanNETs, although some studies have examined the use of cytotoxic chemotherapy for advanced cases. Other potential therapeutic targets include the somatostatin receptor and the vasculature.

• Therapies targeting mTOR have recently been approved for use in patients with PanNETs. Patients treated with the mTOR inhibitor everolimus showed improved prognosis compared with placebo in a Phase III clinical trial. Clinical trials have not yet examined the correlation of mTOR pathway mutations with response to everolimus.

Notes