Is APC a tumor suppressor gene

Familial adenomatous polyposis (FAP) / MUTYH-associated polyposis (MAP)

Scientific background

The classic familial adenomatous polyposis coli (FAP) becomes autosomal dominant inherited and is due to the appearance of a Large number (> 100 to thousands) of colorectal adenomas (Polyps). As a rule, the polyps appear in the second decade of life; from the age of 35, around 95% of those affected have polyps in classic FAP. Since the probability of malignant degeneration is almost 100%, colectomy is the therapy of choice. Many patients develop further extracolic manifestations (e.g. duodenal or papillary adenomas, pancreatic carcinomas, papillary thyroid carcinomas and hepatoblastomas, hypertrophy of the retinal pigment epithelium, glandular cysts of the stomach). The Gardner Syndrome (adenomatous polyposis coli as well as soft tissue tumors and osteomas) and that Turcot Syndrome (adenomatous polyposis coli and CNS tumors, especially medulloblastomas) are phenotypic variants of the APC-associated polyposis.

In addition to the classic FAP, there is also a milder form of the disease, the attenuated FAP (aFAP). These patients usually develop between 10 to 100 adenomas, which usually develop 10-15 years later than with classic FAP and more proximally on the colon.

The FAP is caused by germline mutations in the APC-Tumor suppressor genes on chromosome 5 (5q21-22). The APC protein plays an important role in the Wnt signaling pathway. Most APC-Mutations (over 80%) are nonsense or frameshift mutations that lead to the functional loss of a APC-Allels lead, approx. 9% are splice mutations. In 5-10% of patients there is a deletion or duplication of the APC-Gens before. Due to a random somatic mutation of the second, still intact APCAllele, there is a loss of heterozygosity (LOH) and thus a total failure of the APC system in the affected epithelial cells. In up to 90% of index patients with classic FAP, pathogenic variants can be found in APC can be detected, whereas with aFAP a causative germline variant is detected in only about 20-30% of the patients.

Another polyposis syndrome that is clinically comparable to attenuated FAP is the MUTYH-associated polyposis (MAP). This disease is caused by germline mutations in the MUTYHGene and is one of the few tumor syndromes that autosomal recessive is inherited. The MUTYH-Gen is involved in base exchange repair (BER). The presence of MAP should be considered if colorectal carcinoma is diagnosed at a young age in individual patients or in siblings whose parents are healthy, or if there is a polyposis syndrome without mutation detection in the APC-Gene.

Molecular genetic differentiation of FAP and MAP is important because of the correct risk assessment and precautionary recommendations. If there is evidence of a APC-Mutation should be started from the age of 10 with annual colonoscopies, if two are detected MUTYH-Mutations from around the age of 18. Due to the increased risk of thyroid cancer, especially in FAP patients, they should have annual sonographies from the age of 15.