Genotype–phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis

<jats:title>Abstract</jats:title><jats:p>Familial adenomatous polyposis (FAP) patients develop various life‐threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the <jats:italic>adenomatous polyposis coli</jats:italic> (<jats:italic>APC</jats:italic>) variant, but few reports provide definitive findings about genotype–phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and <jats:italic>APC</jats:italic> variants. Of 247 FAP patients, 126 patients from 85 families identified to have <jats:italic>APC</jats:italic> germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high‐grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398–1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.</jats:p>