RESUMO
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.
Assuntos
Adenocarcinoma/genética , Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Pólipos Adenomatosos/genética , Éxons/genética , Mutação Puntual/genética , Neoplasias Gástricas/genética , Desequilíbrio Alélico/genética , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Mucosa Gástrica/metabolismo , Ligação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Perda de Heterozigosidade , Masculino , Linhagem , Regiões Promotoras Genéticas/genéticaRESUMO
BACKGROUND/AIMS: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in mismatch-repair genes. Besides a lifetime risk of colorectal cancer averaging 70%-80%, there is an increased risk of extracolonic tumors including gastric cancer. The utility of screening gastroscopy in Lynch syndrome has long been debated. This study aimed to determine the proportion of abnormal gastroscopies among patients screened, including the incidence of gastric cancer and prevalence of precursor lesions. MATERIALS AND METHODS: Charts of patients with mutation-proven Lynch syndrome between January 1, 2004, and December 31, 2014, from the Genetics clinic and Hereditary Gastrointestinal Cancer Clinic of our institution were retrospectively reviewed. RESULTS: A total of 66 Lynch syndrome patients were identified. Thirty-two gastroscopies were performed in 21 (32%) of them. No gastric cancers were found. The prevalence of precursor lesions (Helicobacter pylori gastritis, atrophic gastritis, and gastric intestinal metaplasia) was 19.05%. A family history of gastric cancer was associated with a non-significant increased risk of abnormal gastroscopy, while sex and specific gene involved did not affect the abnormality rate. CONCLUSION: Gastric screening in asymptomatic individuals with Lynch syndrome is probably best reserved for high-risk individuals, based on the family history and perhaps ethnicity as suggested by several governing bodies. Larger studies are required to achieve the statistical power necessary to address this controversial issue.