The Diagnostic Yield of Genetic Testing in Patients With Multiple Colorectal Adenomas: A Specialist Center Cohort Study

Abstract

INTRODUCTION: Adenoma multiplicity is associated with increased colorectal cancer (CRC) risk. The utility of genetic testing in patients with multiple colorectal adenomas (MCRA) remains uncertain. We evaluated the diagnostic yield of mutations in polyposis- and CRC-associated genes in patients with MCRA. METHODS: We performed a cross-sectional review of adult patients with 10–99 cumulative adenomas from the prospective database at the St Mark's Hospital Polyposis Registry and Family Cancer Clinic between 1999 and 2021. Genetic testing was performed for adenomatous polyposis–associated genes, hamartomatous polyposis–associated genes, and nonpolyposis colorectal cancer–associated genes. Clinicopathological outcomes were extracted for multiple logistic regression analysis. RESULTS: Two hundred fifty-nine patients with MCRA (median age 61 [interquartile range 53–69] years) were identified. Sixty-six patients (25.5%) had a pathogenic variant or likely pathogenic variant, with APC and biallelic MUTYH mutations constituting the majority of identified pathogenic variant/likely pathogenic variants. Diagnostic yields were greater than 10% at any adenoma burden. In univariate analysis, higher adenoma burden and younger age were associated with higher yield (both P < 0.0001). In patients with MCRA with 10–19 adenomas without a relevant personal or family history of CRC, the diagnostic yield was nil. In multiple logistic regression analysis, higher adenoma burden, younger age, personal history of CRC, and first-degree familial history of CRC were associated with higher diagnostic yield. DISCUSSION: Diagnostic yield of >10% at any adenoma burden supports current guidance for constitutional genetic testing in patients with MCRA, although the low yield in people older than 60 years with 10–19 adenomas suggests that a stratified approach might be appropriate.