1. Paired Somatic-Germline Testing of 15 Polyposis and Colorectal Cancer–Predisposing Genes Highlights the Role of APC Mosaicism in de Novo Familial Adenomatous Polyposis
- Author
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Conxi Lázaro, Estela Carrasco, Mónica Salinas, Mar Varela, Elia Grau, Napoleón de la Ossa Merlano, Esther Darder, Ares Solanes, Angela Velasco, Teresa Ramón y Cajal, Silvia Iglesias, Sara González, Jesús del Valle, Marta Pineda, Noemí Tuset, Gemma Llort, Judith Balmaña, José Marcos Moreno-Cabrera, Barbara Rivera, Carolina Gómez, Matilde Navarro, Gabriel Capellá, Xavier Matias-Guiu, Joan Brunet, Paula Rofes, and Nuria Dueñas
- Subjects
Adult ,Male ,Genes, APC ,Somatic cell ,Colorectal cancer ,Adenomatous Polyposis Coli Protein ,Germline ,Pathology and Forensic Medicine ,Familial adenomatous polyposis ,Cohort Studies ,Young Adult ,medicine ,Humans ,Blood test ,Genetic Predisposition to Disease ,Genetic Testing ,Gene ,Germ-Line Mutation ,Aged ,medicine.diagnostic_test ,Mosaicism ,business.industry ,High-Throughput Nucleotide Sequencing ,Middle Aged ,medicine.disease ,Phenotype ,digestive system diseases ,Adenomatous Polyposis Coli ,Cancer research ,Etiology ,Molecular Medicine ,Female ,Colorectal Neoplasms ,business - Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome responsible for 1% of colorectal cancers (CRCs). Up to 90% of classic FAPs are caused by inactivating mutations in APC, and mosaicism has been previously reported in 20% of de novo cases, usually linked to milder phenotypic manifestations. This study aimed to explore the prevalence of mosaicism in 11 unsolved cases of classic FAP and to evaluate the diagnostic yield of somatic testing. Paired samples of colorectal polyps, tumors, and/or mucosa were analyzed using a custom next-generation sequencing panel targeting 15 polyposis and CRC-predisposing genes. Whenever possible, the extension of mosaicism to blood or sperm was also examined. Of 11 patients with classic adenomatous polyposis, a mosaic pathogenic variant in APC was identified in 7 (64%). No other altered genes were identified. In two of seven patients (29%), mosaicism was found restricted to colonic tissues, whereas in five of seven patients (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 CRC susceptibility, which highlights the role of APC mosaicism in classic FAP etiology. The results further reinforce the importance of testing target tissues when blood test results are negative.
- Published
- 2021