Project title: Finding the causes of small intestinal neuroendocrine tumors

General Description

Our goal is to find the cause or causes of small intestine neuroendocrine tumors (SI-NETs). Our approach has the potential to identify inherited, somatic genetic, epigenetic and infectious causes of SI-NETs. In addition, we will investigate the cell of origin for these tumors, which could enable the development of cellular or animal models for SI-NETs. These goals are directly aligned with the NETRF’s mission: to understand and ultimately to cure neuroendocrine cancers. Almost all cancers are known to be caused by recurrent genomic alterations, but the molecular cause or causes of small intestinal neuroendocrine tumors (SI-NETs) remain unknown—with the only known genome alteration, loss-of-function mutations of CDKN1B, found in ~8% of SI-NET cases. We aim to apply the increasing power of DNA sequencing technology, coupled with the clinical observation that most sporadic SINETs are multifocal, to analyze germline and somatic genome alterations in sporadic SI-NETs using whole genome sequencing. In addition, we will investigate potential environmental causes, including epigenomic and infectious causes, by whole genome bisulfite sequencing and by computational subtraction of genome and transcriptome sequences, respectively. Furthermore, we plan to analyze candidate cells of origin for SI-NETs using single cell sequencing analysis of SI-NETs and neuroendocrine cells in neighboring pre-malignant proliferative lesions. These studies offer the potential to discover molecular causes of SI-NETS using a suite of approaches that we will deploy here for the first time in the study of this disease.