Optimizing Genetic Testing Strategy for Suspected Attenuated Adenomatous Polyposis: Effective Solutions in Public Health Systems

BACKGROUND Attenuated familial adenomatous polyposis (AFAP) and MUTYH-associated polyposis (MAP) represent key hereditary attenuated adenomatous polyposis syndromes, with APC and MUTYH being the associated genes. While guidelines recommend genetic testing based on polyp count for diagnosing these syndromes, age is often overlooked despite its influence on polyp prevalence. AIM To enhance genetic testing strategies for suspected attenuated adenomatous polyposis by combining polyp count and age in a probability calculator. METHODS Retrospective study of adult patients referred to NGS genetic testing for suspected attenuated adenomatous polyposis (accumulated history of <100 adenomas) (discovery cohort, N=138). Data collected included age, adenoma count at the time of genetic testing, and test results. Multivariable logistic regression model was developed to link a positive genetic test result with age and adenoma count. The model was externally validated with populations from two tertiary hospitals in our region (validation cohort, N=259). RESULTS In the discovery cohort, 13 (9.4%) patients tested positive for pathogenic mutations. Positive cases were younger (odds ratio (OR): 0.91, 95% confidence interval (95%IC): 0.86-0.96) and developed more adenomas (OR: 1.08, 95%IC: 1.04-1.13) compared to negative cases. The logistic regression model combining age and polyp count demonstrated an AUC of 0.92. Using a cutoff probability of 3.5%, the model achieved 100% sensitivity and 58% specificity in identifying positive cases. In the external validation, the model accurately predicted 14 out of 16 positive cases (88%). The remaining two positive cases were a patient with an AXIN2 mutation in heterozygosis, and a patient with a NTHL1 mutation in homozygosis. Performance evaluation of both hospitals yielded AUC values of 0.77 and 0.90. CONCLUSIONS Older individuals, particularly those with few polyps, may have diminished chances of detecting hereditary syndromes. Incorporating age as a criterion for genetic testing referral has the potential to refine patient selection and improve cost-effectiveness. Core tip This retrospective muli-center observational study aims to investigate the weight of age and polyp count on patients diagnosed with hereditary attenuated adenomatous polyposis syndrome compared to those with sporadic polyposis. Base on this, a probability calculator has been developed to enhance the efficiency and cost-effectiveness of genetic testing protocols for attenuated adenomatous polyposis syndromes within public health systems.