Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour

Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour

1. Oriol Calvete1,3, 
2. Jose Reyes4, 
3. Sheila Zuñiga5, 
4. Beatriz Paumard-Hernández1,
5. Victoria Fernández1, 
6. Luís Bujanda6, 
7. María S. Rodriguez-Pinilla7, 
8. Jose Palacios8,
9. Damian Heine-Suñer9, 
10. Siddharth Banka10, 
11. William G. Newman10, 
12. Marta Cañamero2,†,
13. D. Mark Pritchard11 and 
14. Javier Benítez1,3,*

+Author Affiliations

1. ¹Human Genetics Group and
2. ²Histopathology Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain,
3. ³Network of Research on Rare Diseases (CIBERER), Madrid 28029, Spain,
4. ⁴Department of Gastroenterology, Hospital INCA, Majorca 07300, Spain,
5. ⁵Department of Bioinformatics, Sistemas Genómicos, Valencia 46980, Spain,
6. ⁶Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Biomedical Research Center, and CIBEREHD, Universidad del País Vasco, San Sebastián 20080, Spain,
7. ⁷Pathology Department, Fundación Jiménez Díaz, Madrid 28040, Spain,
8. ⁸Pathology Department, Hospital Ramón y Cajal. Madrid 28034, Spain,
9. ⁹Genetics Department, Hospital Universitario Son Espases, Majorca 07120, Spain,
10. ¹⁰Centre for Genomic Medicine, University of Manchester and Central Manchester University Hospital NHS Foundation Trust, Manchester M13 9WL, UK and
11. ¹¹Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK

1. ↵*To whom correspondence should be addressed at: Spanish National Cancer Research Center, (CNIO), Melchor Fernández Almagro, 3. 28029, Madrid, Spain. Tel: +34 912246911; Fax: +34 912246911; Email: jbenitez@cnio.es

1. ↵† Present address: Roche Pharmaceutical Research and Early Development, Translational Medicine Oncology Roche Innovation Center. 82377 Penzberg, Germany.

• Received November 13, 2014.
• Accepted February 6, 2015.

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.

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