title: Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour.
abstract: Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.
authors: Human Genetics Group and Network of Research on Rare Diseases (CIBERER), Madrid 28029, Spain.
authors: Oriol
authors: O
authors: Calvete
authors: Department of Gastroenterology, Hospital INCA, Majorca 07300, Spain.
authors: Jose
authors: J
authors: Reyes
authors: Department of Bioinformatics, Sistemas Genómicos, Valencia 46980, Spain.
authors: Sheila
authors: S
authors: Zuñiga
authors: Human Genetics Group and.
authors: Beatriz
authors: B
authors: Paumard-Hernández
authors: Human Genetics Group and.
authors: Victoria
authors: V
authors: Fernández
authors: Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Biomedical Research Center, and CIBEREHD, Universidad del País Vasco, San Sebastián 20080, Spain.
authors: Luís
authors: L
authors: Bujanda
authors: Pathology Department, Fundación Jiménez Díaz, Madrid 28040, Spain.
authors: María S
authors: MS
authors: Rodriguez-Pinilla
authors: Pathology Department, Hospital Ramón y Cajal. Madrid 28034, Spain.
authors: Jose
authors: J
authors: Palacios
authors: Genetics Department, Hospital Universitario Son Espases, Majorca 07120, Spain.
authors: Damian
authors: D
authors: Heine-Suñer
authors: Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospital NHS Foundation Trust, Manchester M13 9WL, UK and.
authors: Siddharth
authors: S
authors: Banka
authors: Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospital NHS Foundation Trust, Manchester M13 9WL, UK and.
authors: William G
authors: WG
authors: Newman
authors: Histopathology Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors: Marta
authors: M
authors: Cañamero
authors: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
authors: D Mark
authors: DM
authors: Pritchard
authors: Human Genetics Group and Network of Research on Rare Diseases (CIBERER), Madrid 28029, Spain, jbenitez@cnio.es.
authors: Javier
authors: J
authors: Benítez
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018358:Neuroendocrine Tumors / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013274:Stomach Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: C000591756:ATP4A protein, human; D017506:H(+)-K(+)-Exchanging ATPase