Point mutations in exon 1B of APC reveal gastric adenocarcinoma and proximal polyposis of the stomach as a familial adenomatous polyposis variant

Gastric adenocarcinoma and proximal polyposis of the stomach is an autosomal dominant cancer predisposition syndrome of fundic gland polyposis with a significant risk of gastric adenocarcinoma. We mapped the gene to 5q22 and found loss of heterozygosity (LOH) only on 5q in fundic gland polyps from affected individuals. Sanger sequencing revealed novel point mutations in APC promoter 1B that co-segregated with disease. All three mutations reduced binding of YY1, and all three mutations showed abrogated activity of the APC promoter 1B luciferase assays. Whole genome sequencing of fundic gland polyps without 5q LOH identified somatic truncating mutations in APC. Fourteen fundic gland polyps from six members of Family 1 were obtained during gastrectomies and snap frozen. ‘Book end’ sections stained with haematoxylin and eosin (H&E) were reviewed by a gastrointestinal pathologist (MB) to estimate the percentage of fundic gland polyps .