Familial adenomatous polyposis (FAP) is an autosomal dominant disorder related to germline mutations of the
adenomatous polyposis coli (APC) gene. It is characterized by the detection of numerous
adenomatous polyps that, if untreated, develop into
colorectal cancer. We studied an Italian family with FAP history and the related
colorectal tumor sample of the proband. Sequencing analysis of blood samples revealed the presence of a never-reported germline mutation in the APC gene (exon 15): an heterozygous G deletion at position c.2126 resulting in a
premature stop codon (p.Gly721GlufsX6) and in a truncated
protein. This mutation was also identified in the
colorectal tumor tissue, together with a second known pathogenic heterozygotic somatic mutation, c.4348C>T (p.Arg1450X), which generates a premature truncated
protein. The novel identified germline mutation is therefore related to FAP and, in accordance with Knudson's "two hit" hypothesis, can be considered the first event predisposing to the insurgence of
colorectal cancer in these patients. The somatic hit inactivating the second allele of the APC gene is located in the mutation cluster region of the gene; this is not a random event since it depends on the position of the germline mutation. The inactivation of APC generates the neoplastic growth advantage to the cell.