Genetic Drivers of Ileal Neuroendocrine Tumors

SIMPLE SUMMARY: Although 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. 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.