Genetic Drivers of Ileal Neuroendocrine Tumors

Abstract

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.

Keywords: ileal; neuroendocrine.

Figure 1

Epithelial cells of the ileum, including the rare serotonin-producing enterochromaffin cells (red cells) that are the origins of ileal neuroendocrine tumors.

Figure 2

A working model for genetic events that lead to multifocal ileal NETs. Notably, these alterations are not caused by point mutations, which are rare in I-NETs. Overexpression of the growth factor IGF2 across a large region of the ileum occurs due to zonal loss of imprinting, which should increase the proliferation of enterochromaffin cells (red) in a number of intestinal crypts. Chromosome 18 loss decreases expression of resident gene MIR1-2, which normally suppresses CDK4 to maintain the RB1 tumor suppressor pathway. No recurrent genetic cause for mTOR activation has been elucidated in I-NETs, but mTOR inhibitors are clinically beneficial for I-NET patients. Even after tumorigenic events occur, the growth of primary ileal NETs often remains slow, possibly due to local production of the growth inhibitor somatostatin by neighboring enteroendocrine cells, which are shown in purple.

Figure 3

The number of pubmed references for the search terms “ileal + neuroendocrine + tumors” is shown by year using a blue line, and is compared to the pubmed references for the search terms “pancreatic + neuroendocrine + tumors“ (orange line). Ileal neuroendocrine tumors are actually more common in the clinic, but draw less research interest and less research funding due to a lack of cell line models, mouse models, and recurrently mutated genes. We speculate that recent discoveries for generating I-NET spheroids and mice, as well as new information about I-NET driver genes, will increase I-NET research interest in the future. Also noted are the years in which some of the key basic science results were published for each tumor type. The ileal neuroendocrine tumor references can be found in this paper; pancreatic neuroendocrine tumor references can be found in a separate review [125].