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.

Protonpumpehemmere og magekreft

“…All four developed gastric tumours at the age of about 30 years (9). Three of these tumours were classified as ECL cell carcinoids, the fourth as an adenocarcinoma (9). However, the adenocarcinoma was positive for the somatostatin-2 receptor which suggests that it is probably a neuroendocrine carcinoma.…”

“…The paper describes ten siblings, four of whom are homozygous for a mutation in one of the genes coding for the proton pump and have thus been anacidic and hypergastrinemic from birth. All four developed gastric tumours at the age of about 30 years (9). Three of these tumours were classified as ECL cell carcinoids, the fourth as an adenocarcinoma (9).…”

“…We have therefore claimed that hypergastrinemia secondary to profound inhibition of acid secretion would, in the long term, necessarily increase the risk of gastric cancer (8). A paper elegantly showing that hypergastrinemia alone induces malignant tumours also in man, has recently been published (9). The paper describes ten siblings, four of whom are homozygous for a mutation in one of the genes coding for the proton pump and have thus been anacidic and hypergastrinemic from birth.…”

The Rise and Rise of Exome Sequencing

“…In addition to identifying somatic driver mutations for sporadic cancer, exome sequencing also succeeded in revealing new genes for the familial form of cancer [37,38,39,40]. Notably, it was applied to sequence 51 individuals with multiple colonic adenomas from 48 families identifying a homozygous germline non-sense mutation in the base-excision repair gene, namely NTHL1 .…”

Identification of novel hereditary cancer genes by whole exome sequencing

“…There is growing evidence that the recessive model of inheritance also plays a role in cancer susceptibility. Biallelic mutations have already been discovered for a number of rare cancer syndromes [34,48,91,94,96,156]. Modeling of inheritance suggests that patients with rare homozygous germline defects are unlikely to report family history [157], therefore the continuing emphasis on members of cancer families (Table 1) may further compromise the discovery of recessive genes.…”