title: A knockin mouse model for human ATP4aR703C mutation identified in familial gastric neuroendocrine tumors recapitulates the premalignant condition of the human disease and suggests new therapeutic strategies.
abstract: By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4a(R703C) mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion.
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid 28029, Spain.
authors.forename: Oriol
authors.identifier: 0000-0002-2623-2876
authors.initials: O
authors.lastname: Calvete
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: D Mark
authors.initials: DM
authors.lastname: Pritchard
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Barroso
authors.affiliation: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid 28040, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Oteo
authors.affiliation: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid 28040, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Morcillo
authors.affiliation: Transgenic Mice Core Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Vargiu
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Dodd
authors.affiliation: Animal Facility Core Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Gastroenterology, Hospital INCA, Majorca 07300, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Reyes
authors.affiliation: Transgenic Mice Core Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain sortega@cnio.es jbenitez@cnio.es.
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid 28029, Spain sortega@cnio.es jbenitez@cnio.es.
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
mesh_terms: D000740:Anemia / Q000097:blood / Q000150:complications / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005744:Gastric Acid / Q000378:metabolism; D005755:Gastrins / Q000097:blood; D055879:Gene Knock-In Techniques; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D006851:Hydrochloric Acid / Q000494:pharmacology; D006965:Hyperplasia; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D018358:Neuroendocrine Tumors / Q000097:blood / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy*; D010641:Phenotype; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000097:blood / Q000235:genetics* / Q000517:prevention & control / Q000628:therapy*
chemical_list: D005755:Gastrins; C000591756:ATP4A protein, human; D017506:H(+)-K(+)-Exchanging ATPase; D006851:Hydrochloric Acid
keywords: ATP4a; Achlorhydria; Gastric carcinoids; Hypergastrinemia; Oxyntic glands