Prevalence and consequences of APC mosaicism in patients with colorectal adenomas

Background and aimsA substantial proportion of patients with adenomatous polyposis have no germline pathogenic variant in APC. The aim of this study was to determine the prevalence of APC mosaicism in these patients with unexplained polyposis and to draft guidelines for APC mosaicism testing and surveillance. MethodsAPC mosaicism was analyzed by targeted Next-Generation sequencing in 542 patients with a broad spectrum of polyposis phenotypes. ResultsThe rate of APC mosaicism was 9.4%. This rate was 14.3% (46/322) in patients who meet the scope of national hereditary polyposis testing guidelines ([≥]10 adenomas before the age of 60 or with [≥]20 adenomas before the age of 70). In patients who do not meet the scope of national guidelines, the detection rate was 2.3% (5/219). In patients with [≥]20 adenomas before the age of 60, or [≥]30 adenomas before the age of 70 the detection rate was [≥]10%. Of 34 mosaic patients who underwent an esophagogastroduodenoscopy, 26% were diagnosed with gastroduodenal polyps. In one patient, the mosaic variant was detected in semen, but none of the children tested in this cohort inherited the mosaic variant. ConclusionWe recommend APC mosaicism testing at least in patients negative for germline pathogenic variants with (1) [≥]20 adenomas before the age of 60 or (2) [≥]30 adenomas before the age of 70. Regular colonoscopy and at least one gastroduodenoscopy should be offered to APC mosaics, with frequency of follow-up based on findings. Offering germline testing for offspring should be considered.