Cancer Risks in Attenuated and Classical Familial Adenomatous Polyposis: A Nationwide Cohort with Matched, Non-Exposed Individuals Cancer and surgery in AFAP and FAP patients

Introduction: Familial adenomatous polyposis (FAP) is caused by pathogenic variants in the APC gene. FAP is usually categorized according to phenotype: classical FAP (CFAP) and attenuated FAP (AFAP); the latter is considered to have a milder disease course. We aimed to assess the risk of overall and specific cancers in CFAP and AFAP patients compared to matched, non-exposed individuals. Methods: All known Danish FAP patients were classified as either CFAP or AFAP and assigned four matched, non-exposed individuals. The risk of overall and specific cancers, and mortality were analyzed. Results: The analysis included 311 CFAP patients, 134 AFAP patients, and 1,600 non-exposed individuals. The overall cancer risk was significantly higher for both CFAP and AFAP patients than for non-exposed individuals, with hazard ratios (HR) of 4.77 (95% confidence interval (CI), 3.61-6.32; P<0.001) for CFAP and 3.22 (95% CI, 2.16-4.80; P<0.001) for AFAP. No significant difference was observed when comparing CFAP and AFAP (HR=1.48; 95% CI, 0.98-2.25; P=0.0646). The HR of colonic cancer was 2.16 (95% CI, 0.99-7.72; P=0.0522) and 2.72 (95% CI, 1.19-6.22; P=0.0177 for CFAP and AFAP), respectively compared to non-exposed and did not differ between CFAP and AFAP patients (HR=0.80; 95% CI, 0.32-2.00; P=0.6278). Mortality was significantly higher in CFAP (HR=2.96; 95% CI, 2.04-4.28; P<0.001), but not in AFAP (HR=1.40; 95% CI, 0.73-2.69; P=0.311). Conclusion: Nationwide data reveal differing risk profiles for specific cancers and mortality in AFAP and CFAP compared to non-exposed individuals. The cancer burden of AFAP necessitates consistent monitoring of these patients.