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: PanNET; genetics; islet cell tumor; mutation; pancreatic neuroendocrine tumor; sequencing.

Figure 1

Loss of ATRX or DAXX function in pancreatic neuroendocrine tumors (PanNETs) with mutated ATRX or DAXX genes. The wild-type proteins are localized to the nucleus, whereas mutations in these genes correlate with loss of nuclear protein expression. A) Immunolabeling for ATRX demonstrating loss of nuclear expression in neoplastic cells, while expression is retained in stromal cell nuclei in well-differentiated PanNET with mutated ATRX. B) Immunolabeling for DAXX of the same PanNET demonstrating nuclear expression.

Figure 1

Loss of ATRX or DAXX function in pancreatic neuroendocrine tumors (PanNETs) with mutated ATRX or DAXX genes. The wild-type proteins are localized to the nucleus, whereas mutations in these genes correlate with loss of nuclear protein expression. A) Immunolabeling for ATRX demonstrating loss of nuclear expression in neoplastic cells, while expression is retained in stromal cell nuclei in well-differentiated PanNET with mutated ATRX. B) Immunolabeling for DAXX of the same PanNET demonstrating nuclear expression.

Figure 2

Schematic representation of the mammalian target of rapamycin (mTOR) signaling pathway and crosstalk with the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway. The mTOR protein is present in two different complexes (mTORC1 and mTORC2) that are activated through two different signaling cascades. MTORC1 is the principal target of rapamycin analogs (rapalogs), including everolimus, while mTORC2 seems not to be sensitive to these agents. Inhibition of mTORC1 by everolimus might cause a lack of inactivation of IRS-1, resulting in an upregulation by feedback loop mechanisms of the PI3K and MAPK pathways. This seems to be one of the main mechanisms that leads to the development of resistance against mTOR inhibitors. (#) Genes with germline mutations characterizing inherited syndromes with predisposition to PanNETs. (*) Genes with somatic mutations found in sporadic PanNETs. Other abbreviations: 4E-BP1, eIF4E-binding protein 1;EGFR, epidermal growth factor receptor; ERK, extracellular signal–regulated kinase; IGFR, insulin- like growth factor receptor; IRS1, insulin receptor substrate 1; MEK, MAP–ERK kinase; PIP2, phosphatidylinositol (4,5)-biphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PTEN, phosphatase and tensin homolog deleted at chromosome; S6K1, p70 S6 kinase 1; TSC, tuberous sclerosis complex.