The Genetics of Neuroendocrine Tumors: A Brief Overview

Citation: Helm M, Joseph S (2017) The Genetics of Neuroendocrine Tumors: A Brief Overview. J Clin Epigenet. Vol. 3 No. 3:33 Introduction Neuroendocrine cells were discovered in 1870 by Rudolph Heidenhain, who noted that they could lead to tumors. Siegfried Oberndorfer introduced the term carcinoid in 1907. Since that time numerous scientists have described tumors that secreted hormones causing a variety of symptoms. In 1924 Seale Harris described insulinoma, in 1942 William Becker described glucagonoma, and in 1955 Zollinger and Ellison described gastrinoma. The first reported case of CCK-oma was described in 2013. The term Neuroendocrine tumors (NET) encompasses a wide variety of neoplasms commonly secrete neuropeptides [1].


Introduction
Neuroendocrine cells were discovered in 1870 by Rudolph Heidenhain, who noted that they could lead to tumors. Siegfried Oberndorfer introduced the term carcinoid in 1907. Since that time numerous scientists have described tumors that secreted hormones causing a variety of symptoms. In 1924 Seale Harris described insulinoma, in 1942 William Becker described glucagonoma, and in 1955 Zollinger and Ellison described gastrinoma. The first reported case of CCK-oma was described in 2013. The term Neuroendocrine tumors (NET) encompasses a wide variety of neoplasms commonly secrete neuropeptides [1].

Epidemiology
The incidence of Neuroendocrine Tumors (NET) are increasing worldwide. In 1973, the incidence in the United States was 1.9 cases per 100,000. In 2004, the incidence had increased to 5.25 per the SEER database. These same trends are occurring in numerous other countries [1].
While there has been no link between PPI use and NET, there is a temporal correlation between the increased use of proton pump inhibitors (PPI) and the increased incidence of NET. Timoprazole was discovered to inhibit acid secretion irrespective of stimulus in 1975. Further studies revealed enlargement of the thyroid gland due to reduced iodine uptake as well as atrophy of the thymus. Omeprazole began trials in 1980 and was released worldwide in 1988. It quickly became the biggest selling pharmaceutical in history. The long-term use of PPI has been shown to significantly increase gastrin levels. Gastrin stimulates neuroendocrine cell growth and may increase the malignant potential of NE cells [1].  Menin has been shown to accumulate in the nucleus of most cells. The C-terminal quarter has at least 3 nuclear localization signals. In non-dividing cells menin is in the nucleus, while in dividing cells it is in the cytoplasm. Mutations of menin have been found to be missing at least one nuclear localization signal which may cause their accumulation in the cytoplasm. Menin appears to interact with several proteins involved in transcriptional regulation, genome stability, cell division and proliferation; however its exact function is still unknown. Menin has also been shown to directly bind double stranded DNA. This binding may play a role in epigenetic regulation via histone methylation or acetylation [6][7][8][9][10][11][12][13][14][15].

MEN 4
MEN 4 is associated with and pituitary adenomas, pancreatic islet-cell hyperplasia, bilateral pheochromocytomas, paraganglionomas, and cataracts [2,12]. MEN 4 is mapped to CDNK1B gene mutation, which encodes the 195 amino acid cyclin dependent kinase inhibitor (CK1) p27 kip1 . In a naturally occurring rat model, this syndrome, called MENX, is autosomal recessive. This CDNK1B mutation resulted in an absence of p27 protein in tumor cells. P27 belongs to the Cip/Kip family of cyclin dependent kinases. It binds and inhibits cyclin E-CDK2 which stops or slows cell cycle progression at G1. CDNK1B is located on chromosome 12p13. In humans, this mutation is autosomal dominant unlike MENX in rats [2, 12,13]. VHL gene is a tumor suppressor gene on chromosome 3p25. Approximately 20% of patients have large germline mutations, 27% have missense mutations, and 27% have nonsense or frameshift mutations. Finally, 20% of patients will not have an identifiable mutation on analysis. VHL protein binds elongin B and C and degrades the alpha subunit of hypoxia-inducible factor (HIF). Normal function of this protein seems to inhibit transcription elongation. Lack of normal alpha HIF degradation produces over stimulation of blood vessel growth and tumor development [14][15][16][17].

Conclusions
Neuroendocrine tumors are rare however the incidence is increasing. Identification of syndromes that lead to numerous different NET in the same patients has led to a better understanding of NET expression. Investigation of these syndromes has led to a better understanding of genetic mutations and the disease they are linked to.
1. MEN 1 syndrome is linked to the autosomal dominant MEN1 gene. The complete function of the menin protein is unknown currently, however inactivation has been shown to cause increased cell division and increased transcriptional mutations.
2. MEN 2 syndromes have been linked to the autosomal dominant RET proto-oncogene. RET codes for a tyrosine kinase receptor that binds GDNF and stimulates growth.
RET mutations cause a gain in function that overstimulates growth. MEN 2 syndromes can be differentiated based on their RET mutation, phenotype variance and loss of heterzygosity.
3. MEN 4 is a newer syndrome associated with changes to the acid cyclin dependent kinase inhibitor and is mapped to mutations in the CDNK1B gene. This mutation causes loss of p27 protein which allows cells to continue to proliferate. It is autosomal dominant in humans.
4. VHL was previously not associated with NET however