Truncating Adenomatous Polyposis Coli Mutations Serve as a Biomarker for Advanced Tumor Stage in Iranian Patients with Familial Colorectal Cancer.

The Adenomatous Polyposis Coli gene (APC) is a key tumor suppressor in colorectal cancer (CRC). While germline mutations in its Mutation Cluster Region (MCR) are implicated in familial CRC, the prognostic impact of specific mutation types within distinct populations remains poorly characterized. This study sequenced the APC-MCR in 96 Iranian familial CRC patients, 6 disease controls (gastritis/celiac), and 10 healthy controls. Variants were classified per ACMG guidelines. Patients were stratified into four genetic categories: Wild-Type (WT), Variant of Uncertain Significance (VUS) only, Truncating pathogenic/likely pathogenic (P/LP), and Missense P/LP. Associations with clinicopathological features were assessed using Chi-square, Fisher's exact tests, and independent t-tests. OR with 95% CI were calculated. Pathogenic mutations were identified in 39.6% (38/96) of patients and 0% of controls (P < 0.0001). A significant association existed between the mutation type and the tumor stage (P = 0.001). Advanced-stage (III/IV) disease was present in 22.2% of WT, 31.8% of VUS only, 61.3% of Truncating P/LP, and 71.4% of Missense P/LP patients. Truncating P/LP mutations conferred significantly higher odds of advanced-stage disease (OR = 5.54, 95% CI: 1.98-15.51, P = 0.001) versus WT. No significant association was found with age, sex, grade, or tumor location. The type of APC mutation, specifically truncating variants, is a powerful biomarker for advanced tumor stage in Iranian familial CRC, underscoring the critical need for genotype-driven risk stratification.