title: Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.
abstract: Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.
authors.affiliation: Departments of *Pathology and Laboratory Medicine ‡Biostatistics, Lineberger Comprehensive Cancer Center †Department of Medicine, Division of Gastroenterology, University of North Carolina, Chapel Hill, NC 27599-7080 §Department of Surgical Oncology, Lineberger Comprehensive Cancer Center ∥Department of Medicine, Hospital de Occidente, Santa Rosa de Copan ¶Department of Gastroenterology, Hospital Evangelico, Siguatepeque, Honduras.
authors.forename: Olga
authors.initials: O
authors.lastname: Speck
authors.forename: Weihua
authors.initials: W
authors.lastname: Tang
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Morgan
authors.forename: Pei Fen
authors.initials: PF
authors.lastname: Kuan
authors.forename: Michael O
authors.initials: MO
authors.lastname: Meyers
authors.forename: Ricardo L
authors.initials: RL
authors.lastname: Dominguez
authors.forename: Enrique
authors.initials: E
authors.lastname: Martinez
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gulley
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D018278:Carcinoma, Neuroendocrine / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation; D053379:Chromogranin A / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D018740:Genetic Heterogeneity; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D011379:Prognosis; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology / Q000821:virology
chemical_list: C506150:CHGA protein, human; D053379:Chromogranin A; D005755:Gastrins; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human