Paired somatic-germline testing of 15 polyposis and colorectal cancer–predisposing genes highlights the role of APCmosaicism in de novofamilial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers. Up to 90% of classical FAP are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novocases, usually linked to milder phenotypic manifestations. To explore the prevalence of mosaicism in 11 unsolved cases of classical FAP and to evaluate the diagnostic yield of somatic testing. Paired samples of colorectal polyps, tumors and/or mucosa were analyzed using a custom NGS panel targeting 15 polyposis and colorectal cancer-predisposing genes. Whenever possible, the extension of mosaicism to blood or sperm was also examined. Out of 11 patients with classical adenomatous polyposis, a mosaic pathogenic variant in APCwas identified in seven (64%). No other altered genes were identified. In 2/7 (29%) mosaicism was found restricted to colonic tissues, while in 5/7 (71%) it was extended to the blood. Germline affectation was confirmed in one patient. We report the first analysis at a somatic level of 15 genes associated with colorectal cancer susceptibility, which highlights the role of APCmosaicism in classical FAP etiology. The results further reinforce the importance of testing target tissues when blood test results are negative.