Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant

Abstract

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.

Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers

“…Recent large‐scale genomic characterization of gastric tumours reveals frequent somatic mutations to APC in non‐hypermutated chromosomal instable GCs (Cancer Genome Atlas Research, ), which is further supported by an independent patient dataset reporting an even higher incidence of somatic mutations to APC (Cristescu et al , ). Likewise, in gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) patients, mutation analysis and Sanger sequencing successfully mapped point mutations in APC promoter 1B, which was shown to reduce binding of the Yin Yang 1 (YY1) transcription factor and impaired the activity of APC 1B promoter (Li et al , ). Importantly, allelic imbalance of APC is detectable in patient blood and saliva samples, serving as an excellent biomarker for prospective GAPPS patients (Li et al , ).…”

The first European family with gastric adenocarcinoma and proximal polyposis of the stomach: case report and review of the literature

“…Further, voluminous mass of polyps interfered with an effective endoscopic surveillance and no genetic background responsible for GAPPS (3) was known at the time of diagnosis.…”

“…Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) has been identified in only 8 families worldwide (1,2,3). Worthley et al (1) described this syndrome in an Australian white family, an American white family, and a Canadian white family.…”

Hereditäres Magen- und Pankreaskarzinom

“…Kürzlich wurde der zugrunde liegende Gendefekt entschlüsselt: Betroffene Familien weisen Punktmutationen im APCPromotor 1B auf [28]. Das Syndrom wurde in Australien, Kanada und den USA entdeckt.…”