Molecular Genetics of Gastroenteropancreatic Neuroendocrine Tumors
Molecular Genetics of Gastroenteropancreatic Neuroendocrine Tumors
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are usually sporadic; however, familial (inherited) syndromes, such as the multiple endocrine neoplasia 1 (MEN-1) syndrome, von Hippel-Lindau (VHL) syndrome, neurofibromatosis (NF-1), as well as tuberous sclerosis, may be associated with proximal intestinal and pancreatic NETs. For example, 25% of gastrinoma patients have MEN-1 syndrome. Over the last two decades, the genetic basis of tumorigenesis for these familial syndromes has been clearly identified, providing clinicians with useful screening tools for affected families. Also, over the last few years, advanced molecular genetic techniques, such as comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses, have detected some differences in genomic aberrations among various types of NETs. Whether these chromosomic alterations have implications in the treatment of patients and the outcome of the disease is still unclear.
Neuroendocrine tumors (NETs) represent a group of neoplasms arising from neuroendocrine cells of the diffuse endocrine system. They comprise approximately 2% of all malignant tumors of the gastroenteropancreatic (GEP) system. Although characterized by relatively slow tumor growth, they have malignant potential, and most of them are diagnosed when distant (mainly liver) metastases have developed. GEP-NETs include those of the gastrointestinal (GI) tract (GI-NETs), classically known as "carcinoids," and also neuroendocrine pancreatic tumors (NPTs), formerly known as "islet cell tumors."
The management of patients with GEP-NETs is individualized, based mainly on tumor histology and the presence of distal metastases. Surgery remains the only chance of cure, and includes resection of the primary and, if possible, the metastatic lesions. Somatostatin analogs are currently the "gold standard" for controlling the patients' symptoms in cases of functional tumors. In patients with advanced disease, peptide receptor treatment, transarterial hepatic embolization (or chemoembolization), cytotoxic chemotherapy, as well as the new antiangiogenetic agents are the available treatment options in order to control tumor growth.
Most GEP-NETs are sporadic. However, some of them, and especially NPTs, may occur as part of familial (inherited) syndromes, such as the multiple endocrine neoplasia 1 (MEN-1) syndrome, von Hippel-Lindau (VHL) syndrome, neurofibromatosis (NF-1), and tuberous sclerosis (TSC).
Over the last two decades, the genetic basis of tumorigenesis for these familial syndromes has been clearly identified, providing clinicians with useful screening tools for affected families.
On the other hand, ongoing research using new molecular techniques, such as comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses, has tried to identify specific chromosomal abnormalities and genes that are associated with the more common sporadic forms of GEP-NETs.
In this brief review, we present the familial NET syndromes, and clarify the indications for genetic testing in these patients. Also, we summarize the current information regarding genomic patterns that characterize various sporadic GEP-NETs.
Abstract and Introduction
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are usually sporadic; however, familial (inherited) syndromes, such as the multiple endocrine neoplasia 1 (MEN-1) syndrome, von Hippel-Lindau (VHL) syndrome, neurofibromatosis (NF-1), as well as tuberous sclerosis, may be associated with proximal intestinal and pancreatic NETs. For example, 25% of gastrinoma patients have MEN-1 syndrome. Over the last two decades, the genetic basis of tumorigenesis for these familial syndromes has been clearly identified, providing clinicians with useful screening tools for affected families. Also, over the last few years, advanced molecular genetic techniques, such as comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses, have detected some differences in genomic aberrations among various types of NETs. Whether these chromosomic alterations have implications in the treatment of patients and the outcome of the disease is still unclear.
Introduction
Neuroendocrine tumors (NETs) represent a group of neoplasms arising from neuroendocrine cells of the diffuse endocrine system. They comprise approximately 2% of all malignant tumors of the gastroenteropancreatic (GEP) system. Although characterized by relatively slow tumor growth, they have malignant potential, and most of them are diagnosed when distant (mainly liver) metastases have developed. GEP-NETs include those of the gastrointestinal (GI) tract (GI-NETs), classically known as "carcinoids," and also neuroendocrine pancreatic tumors (NPTs), formerly known as "islet cell tumors."
The management of patients with GEP-NETs is individualized, based mainly on tumor histology and the presence of distal metastases. Surgery remains the only chance of cure, and includes resection of the primary and, if possible, the metastatic lesions. Somatostatin analogs are currently the "gold standard" for controlling the patients' symptoms in cases of functional tumors. In patients with advanced disease, peptide receptor treatment, transarterial hepatic embolization (or chemoembolization), cytotoxic chemotherapy, as well as the new antiangiogenetic agents are the available treatment options in order to control tumor growth.
Most GEP-NETs are sporadic. However, some of them, and especially NPTs, may occur as part of familial (inherited) syndromes, such as the multiple endocrine neoplasia 1 (MEN-1) syndrome, von Hippel-Lindau (VHL) syndrome, neurofibromatosis (NF-1), and tuberous sclerosis (TSC).
Over the last two decades, the genetic basis of tumorigenesis for these familial syndromes has been clearly identified, providing clinicians with useful screening tools for affected families.
On the other hand, ongoing research using new molecular techniques, such as comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses, has tried to identify specific chromosomal abnormalities and genes that are associated with the more common sporadic forms of GEP-NETs.
In this brief review, we present the familial NET syndromes, and clarify the indications for genetic testing in these patients. Also, we summarize the current information regarding genomic patterns that characterize various sporadic GEP-NETs.