Classical familial adenomatous polyposis (FAP) is an inherited autosomal dominant condition characterized by the appearance of multiple (>100 to thousands) colorectal adenomas (polyps). As a rule, the polyps appear in the second decade of life, and from the age of 35 years about 95% of those affected by classical FAP have polyps. Since the probability of malignant degeneration is almost 100%, a colectomy is the therapy of choice. Extracolonic manifestations can also be observed (e.g., duodenal or papillary adenomas, pancreatic carcinomas, papillary thyroid carcinomas and hepatoblastomata, retinal pigment epithelium hypertrophy, glandular cysts of the stomach). Gardner syndrome (adenomatous polyposis and soft tissue tumors and osteomata) and Turcot syndrome (adenomatous polyposis and CNS tumors, especially medulloblastomata) are phenotypic variants of APC-associated polyposis.
Besides the classical form of FAP there is also a milder form of the disease, attenuated FAP (aFAP). These patients usually develop between 10 and 100 adenomas, which generally occur 10-15 years later than in classical FAP and have a more proximal location in the colon.
FAP is caused by germline variants in the APC tumor suppressor gene on chromosome 5 (5q21-22). The APC protein plays an important role in the Wnt signaling pathway. Most of the pathogenic APC variants (over 80%) are nonsense or frameshift mutations that lead to the functional loss of an APC allele, approximately 9% are splice mutations. In 5-10% of patients there is a deletion or duplication of the APC gene. A random somatic change in the second, still intact APC allele leads to a loss of heterozygosity (LOH) and thus to a total failure of the APC system in the affected epithelial cells. Pathogenic APC variants can be detected in up to 90% of index patients with classical FAP, whereas in aFAP a pathogenic germline variant is only detected in about 20-30% of patients.
Another polyposis syndrome clinically associated with attenuated FAP is MUTYH-associated polyposis (MAP). This disease is caused by germline mutations in the MUTYH gene and is one of the few autosomal recessive tumor syndromes. The MUTYH gene is involved in base exchange repair (BER). The presence of MAP should be considered when a colorectal carcinoma is diagnosed at a young age in an individual patient or in siblings whose parents are healthy, or in the presence of a polyposis syndrome without evidence of a pathogenic variant in the APC gene.
Molecular genetic differentiation between FAP and MAP is important for correct risk assessment and precautionary recommendations. If one pathogenic APC variant is detected, annual colonoscopies should begin from the age of 10, and if two pathogenic MUTYH variants are detected, the annual procedure should start from about the age of 18. Due to an increased risk of thyroid carcinoma in FAP patients, they should have an annual sonography from the age of 15.
In a few patients with suspected adenomatous polyposis syndrome but without evidence of a pathogenic germline variant in the APC or MUTYH genes, pathogenic variants in the POLE and POLD1 genes can be detected. Heterozygous missense variants in these genes can lead to the development of multiple colorectal adenomas (<100 polyps), the formation of colorectal carcinomas and the development of endometrial carcinomas. Rarely, pathogenic POLE and POLD1 variants can be detected in patients with Lynch syndrome-like phenotype and without evidence of a change in the MMR genes.
The so-called polymerase proofreading-associated polyposis (PPAP) is an inherited autosomal dominant condition and is caused by pathogenic germline variants in the POLE or POLD1 genes, which code for the DNA polymerase Epsilon (pole E) or Delta (pole D). Changes in the exonuclease domain of these polymerases can lead to impaired proofreading during DNA replication, and possibly to increased base substitution and the development of hypermutated intestinal tumors.
An increased incidence of adenomatous polyps is also seen in the autosomal recessive inherited NTHL1-associated tumor syndrome. This is caused by pathogenic germline variants in the NTHL1 gene, which codes for a DNA glycosylase and plays an important role in base excision repair (BER signaling pathway). Causal variants have so far been detected in only very few cases (<1%). The influence of pathogenic biallelic MSH3 germline variants as the cause of another autosomal recessive polyposis subtype is currently being discussed.
Leitlinienprogramm Onkologie: S3-Leitlinie Kolorektales Karzinom, Langversion 2.1, 2019 / Jasperson et al. 2017, APC-Associated Polyposis Conditions, GeneReviews®, www.ncbi.nlm.nih.gov/books/ NBK1345/ / Lorans et al. 2018, Clinical Colorectal Cancer 17:e293 / Weren et al. 2018, J Pathol 244:135 / Brosens et al. 2016, Adv Exp Med Biol 908:347 / Waller et al. 2016, J Pediatr Genet 5:78 / Syngal et al. 2015, Am J Gastroenterol 110:223 / Kerr et al. 2013, J Mol Diag 15, 1:31 / Spier et al. 2014, Int. J. Cancer 137:320 / Palles et al. 2013, Nat Genet 45(2):136 / Nielsen et al. 2012, MUTYH-Associated Polyposis, GeneReviews®, www.ncbi.nlm.nih.gov/books/NBK107219/ / Gryfe 2009, Clin Colon Rectal Surg. 22:198
Hereditary gastrointestinal polyposis syndromes are rare hereditary syndromes associated with an increased risk of colon tumors and are the cause of about 1% of all colorectal cancers. They are characterized by the occurrence of multiple polyps in the gastrointestinal tract and can cause further intestinal and extraintestinal manifestations.
Adenomatous polyps occur primarily in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). The disease is caused by pathogenic germline variants in the APC or MUTYH gene. The molecular genetic differentiation of both diseases is important for a correct risk assessment due to the different inheritance. In a few patients with (adenomatous) polyps and inconspicuous APC and MUTYH findings, pathogenic variants in the genes POLE, POLD1 (polymerase proofreading associated polyposis, PPAP) or NTHL1 (NTHL1-associated tumor syndrome) can be detected.
Hamartomatous polyposis syndromes (HPS), which are sometimes difficult to distinguish from adenomatous syndromes, include juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS) and Cowden syndrome (PTEN hamartoma tumor syndrome, PHTS). All three polyposis syndromes are very rare and follow an autosomal dominant inheritance pattern. Other syndromes in which hamartomatous polyps can also (rarely) manifest are Birt-Hogg-Dubé syndrome (FLCN gene), MEN2 syndrome (RET gene) and neurofibromatosis type 1 (NF1 gene).
Serrated polyps of the colon are characteristic of hyperplastic polyposis syndrome (HPS), the genetic cause of which is not yet sufficiently understood. Currently, a correlation between disease occurrence and the detection of germline variants in the RNF43 gene is being considered. Another polyposis syndrome associated with multiple colonic polyps of different entities is hereditary mixed polyposis (HMPS). Rarely occurring duplications of the regulatory region of the GREM1 gene seem to correlate with this polyposis syndrome.
Valle et al. 2019, Mol Aspects Med 69:10 / Lorans et al. 2018, Clin Colorectal Cancer 17:e293 / Jelsing et al. 2014, Orphanet J Rare Dis 9:101 / Shussman and Wexner 2014, Gastroenterol Rep 2:1 / Huber et al. 2013, J Gastroint Dig System 3:155 / Aretz et al. 2010, Dtsch Arztebl Int 107:163
*CNV analysis only
Genes in bold are recommended by International guidelines, including German expert panels and/or have been more often associated with specific cancers.