title: Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors.
abstract: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs.
  
  
  
  We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA.
  
  
  
  We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs.
  
  
  
  Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease.
authors.affiliation: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yoshitatsu
authors.initials: Y
authors.lastname: Sei
authors.affiliation: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jianying
authors.initials: J
authors.lastname: Feng
authors.affiliation: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Joanne
authors.initials: J
authors.lastname: Forbes
authors.affiliation: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Derek
authors.initials: D
authors.lastname: Tang
authors.affiliation: Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Kunio
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hanson
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Martha M
authors.initials: MM
authors.lastname: Quezado
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Marybeth S
authors.initials: MS
authors.lastname: Hughes
authors.affiliation: Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: stevew@mail.nih.gov.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wank
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D004759:Enterochromaffin Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007078:Ileal Neoplasms / Q000235:genetics*; D017403:In Situ Hybridization; D007421:Intestine, Small / Q000166:cytology; D007580:Jejunal Neoplasms / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics*; D018358:Neuroendocrine Tumors / Q000235:genetics*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C069077:BMI1 protein, human; C476884:HOPX protein, human; D018398:Homeodomain Proteins; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D025521:Tumor Suppressor Proteins; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase; D063150:Polycomb Repressive Complex 1
keywords: Cancer; Gene Expression; Malignancy; Small Intestine