Clinical management

Gastric fundic gland polyps☆

Gastric cancer (GC) is a newly described cancer risk in Western patients with familial adenomatous polyposis (FAP). Little is known about clinical, endoscopic, and pathologic features associated with FAP-related GC. We compared these features in FAP patients with and without GC.

FAP patients were identified through the David G. Jagelman Inherited Colorectal Cancer Registries Cologene database. FAP patients with GC and randomly selected FAP patients without GC who had undergone at least 2 EGDs were analyzed. Demographic, clinical, endoscopic, and pathologic features were compared.

Ten FAP patients with GC were identified, and 40 age-matched FAP control subjects were selected. No demographic differences were noted between patients and control subjects. All GC cases arose in the proximal stomach among gastric polyposis, with only 2 endoscopically visible. The prevalence of gastric polyposis was similar (100% vs 93%). Endoscopic features associated with GC included a carpeting of gastric polyps (100% vs 22.5%), solitary polyps >20 mm (100% vs 0%), and a polypoid mound of polyps (80% vs 0%; all P < .001). GC patients had a higher prevalence of gastric adenomas (30% vs 5%, P = .048) and polyps with high-grade dysplasia, including fundic gland polyps (50% vs 10%, P = .01) and pyloric gland adenomas (20% vs 0%, P = .037).

We identified endoscopic features and advanced pathology present in the stomachs of Western patients with FAP who developed GC. Upper GI surveillance in FAP should include the stomach and awareness of features associated with GC. Optimal approaches to treatment of gastric polyposis and methods of identification of early GC precursors in FAP are needed.

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.