Abstract
Simple SummaryAlthough ileal neuroendocrine tumors are the most common tumors of the small intestine, they are not well-defined at the genetic level. Unlike most cancers, they have an unusually low number of mutations, and also lack recurrently mutated genes. Moreover ileal NETs have been difficult to study in the laboratory because there were no animal models and because cell lines were generally unavailable. But recent advances, including the first ileal NET mouse model as well as methods for culturing patient tumor samples, have been described and have already helped to identify IGF2 and CDK4 as two of the genetic drivers for this tumor type. These advances may help in the development of new treatments for patients.The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes.
Highlights
Neuroendocrine tumors are the most common types of tumors within the small intestine, with an incidence of 1.05 per 100,000 in the United States [1,2]
Somatostatin is an I-NET inhibitor that is produced by enteroendocrine cells within the ileum but not by cells of the liver, whereas insulin-like growth factor-2 (IGF2) is an activator of I-NET tumorigenesis that is usually produced at higher levels in the liver than in the small intestine
Even though ileal neuroendocrine tumors were included in a large search for cancer-specific DNA methylation markers, I-NETs are not listed among the 50 cancers that can be detected by the Galleri test that emerged from this study [86]
Summary
Neuroendocrine tumors are the most common types of tumors within the small intestine, with an incidence of 1.05 per 100,000 in the United States [1,2]. Cells ofstudies the ileum not be strictly applicable to well-differentiated ileal ure 1) These cells are quite rare: less than 1% of the epithelial cells of the ileum are enterI-NETs arise from serotonin-producing enterochromaffin (EC) cells of the ileum oendocrine, while the serotonin-expressing EC cells are only a subset of the many types (Figure 1). High serotonin tumors secrete related serotonin, that patients can experience elevated serotonin levels expression results in a condition known as carcinoid syndrome, which is characterized along with symptoms related to serotonin vasoactivity. There are cases in which patients have very large liver metastases that express specific I-NET markers such as CDX2, yet the patients lack detectable primary tumors presumably because their primary I-NETs are so small. Somatostatin is an I-NET inhibitor (see section) that is produced by enteroendocrine cells within the ileum but not by cells of the liver, whereas IGF2 is an activator of I-NET tumorigenesis (see below) that is usually produced at higher levels in the liver than in the small intestine
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