Declining Detection Rates for <i>APC</i> and Biallelic <i>MUTYH</i> Pathogenic Variants in Polyposis Patients, Implications for DNA Testing Policy

Abstract

Background: This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account several factors including adenoma count and year of diagnosis. Methods: All application forms used to send patients in for APC and MUTYH mutation analysis between 1992 and 2017 were collected (n=2082). Using this data, possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. Findings: The prevalence of APC mutations significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis and having a first degree family member with more than 10 polyps. Moreover, the chance of finding an APC or MUTYH mutation steadily declined over the past 23 years. Mutations in APC and MUTYH were found in 22% (43/200) of patients with FAP-related extracolonic manifestations, such as duodenal polyps and desmoid tumors. Mutation detection rate were 40% and 10% for respectively patients with >10 adenomas under age 60 and >20 adenomas under age 70. Mutation carriers not falling into these criteria, had FAP-related extracolonic manifestations, colorectal cancer (CRC) below the age of 40, somatic KRAS c.34G>T variant in the tumor or a first-degree family member with >10 adenomas. Interpretation: Adenoma count, age at diagnosis of the adenomas and year of analysis are important predictive factors for APC and MUTYH mutations. Based on our results, APC and MUTYH testing is advised in patients >10 adenomas under age 60 and >20 adenomas under age 70. Almost all FAP and MAP patients who did not meet these criteria showed other characteristics that can be used as an indication to prompt genetic testing. Funding Statement: The authors declare: N/A. Declaration of Interests: The authors state: No competing interest to declare. Ethics Approval Statement: The study was approved by local ethics review boards (P01.019).