APC – Gastric Adenocarcinoma and Proximal Polyposis of the Stomach

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is a rare autosomal dominant cancer-predisposition syndrome characterized by massive fundic gland polyposis with relative sparing of the antrum and lesser curvature, and a significant risk of early-onset gastric adenocarcinoma. Pathogenic single-nucleotide variants in promoter 1B of APC reduce binding of the transcription factor YY1, leading to allele-specific downregulation of APC expression and tumorigenesis, adding GAPPS to the molecular class of APC-associated disorders (PMID:30584346).

GAPPS follows autosomal dominant inheritance with incomplete penetrance. Co-segregation of APC promoter 1B point mutations has been documented in 6 families by Li et al. (PMID:27087319) and further confirmed in 8 Czech families at Masaryk Memorial Cancer Institute (PMID:31409086). Across these cohorts, at least 24 carriers exhibit fundic gland polyposis and dysplasia, with 5 individuals developing gastric adenocarcinoma, supporting strong clinical validity. The c.-191T>C variant has emerged as a recurrent founder allele in Central European families (PMID:31409086).

Three pathogenic promoter 1B variants—c.-191T>C, c.-192A>G, and c.-195A>C—reduce APC transcriptional activity by disrupting the YY1 binding motif. The hotspot c.-191T>C has been reported in at least 8 families of Czech origin (PMID:31409086). No coding APC variants have been implicated in GAPPS, underscoring the critical role of promoter perturbation.

Functional assays demonstrate that promoter 1B variants abrogate YY1 binding and reduce luciferase reporter activity by >50%, and allelic imbalance studies confirm decreased expression of the mutant APC allele in vivo, consistent with a haploinsufficiency mechanism (PMID:27087319).

Clinically, GAPPS presents with innumerable fundic gland polyps that often progress to low- and high-grade dysplasia and early-onset gastric adenocarcinoma; cumulative gastric cancer risk is ~30% by age 50 (PMID:39039610). Endoscopic surveillance alone may fail to prevent malignant transformation, and prophylactic total gastrectomy is recommended for mutation carriers, particularly upon detection of dysplasia.

APC promoter 1B mutations define a distinct autosomal dominant gastric cancer syndrome with strong genetic and moderate functional evidence. Genetic testing for promoter 1B variants (c.-191T>C, c.-192A>G, c.-195A>C) should be incorporated into diagnostic panels for families with proximal gastric polyposis. Key take-home: early identification enables tailored surveillance and prophylactic interventions to mitigate high gastric cancer risk.

References

• American Journal of Human Genetics • 2016 • Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. PMID:27087319
• Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti • 2019 • GAPPS – Gastric Adenocarcinoma and Proximal Polyposis of the Stomach Syndrome in 8 Families Tested at Masaryk Memorial Cancer Institute – Prevention and Prophylactic Gastrectomies. PMID:31409086
• Clinical and Experimental Gastroenterology • 2018 • Gastric adenocarcinoma and proximal polyposis of the stomach: diagnosis and clinical perspectives. PMID:30584346
• Hereditary Cancer in Clinical Practice • 2024 • Gastrointestinal manifestations in patients with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a systematic review with analysis of individual patient data. PMID:39039610

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