FAP is characterized by the development of multiple adenomas in the colorectum, a high risk of CRC, and the existence of extracolonic manifestations. Germline APC mutations causing FAP with an autosomal dominant pattern of inheritance were first described in 1991.8,9 Since then, a great body of evidence on FAP has been generated, including pathophysiology, genetics, clinical phenotype and prevention. In 2002, another polyposis gene was identified, the MUTYH gene, in which biallelic mutations cause an autosomal recessive pattern of inheritance, usually referred to as MUTYH-associated polyposis (MAP).9 Classic FAP is characterized by the presence of hundreds to thousands adenomatous polyps throughout the colon and rectum and an almost 100% risk of CRC. Attenuated FAP (AFAP) is a variant of FAP with a milder disease course, characterized by a reduced number of polyps (10–100), later age at onset, frequently right-sided distribution of polyps and a lower CRC risk (up to 70%).10
In a large cross-sectional study, APC mutations were found in 80% (95% CI, 71–87%) of individuals who had more than 1,000 adenomas, 56% (95% CI, 54–59%) of those with 100–999 adenomas, 10% (95% CI, 9–11%) of those with 20–99 adenomas, and 5% (95% CI, 4–7%) of those with 10–19 adenomas.11 Biallelic MUTYH mutations were found in 2% (95% CI, 0.2–6%) of patients who had more than 1,000 adenomas, 7% (95% CI, 6–8%) of those with 100–999 adenomas, 7% (95% CI, 6–8%) of those with 20–99 adenomas, and 4% (95% CI, 3–5%) of those with 10–19 adenomas.11 Accordingly, a significant number of patients with FAP, especially those with AFAP, carry neither MUTYH nor APC germline mutations. Of note, Palles et al. identified heterozygous germline variants in the POLE and POLD1 genes in individuals with a family history of multiple adenomas and CRC, but no detectable mutations in APC or MUTYH.12
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