Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Polyposis Coli, familial adenomatous polyposis (FAP) / MUTYH associated polyposis (MAP) [D12.6]

OMIM numbers: 175100, 611731 (APC), 608456, 604933 (MUTYH)

Dr. biol. hum. Stefanie Kühner, Dr. med. Dagmar Wahl,
Dr. med. Imma Rost

Scientific Background

Classic familial adenomatous polyposis (FAP) is an autosomal dominant inherited disorder, characterized by the development of numerous colorectal adenomas (polyps). Polyps usually develop in the second decade of life, and by the age of 35 approximately 95% of people with FAP have polyps. Since the probability that malignant degeneration will occur (on average from around 40 years of age) is almost 100%, colectomy is the treatment of choice.

The majority of patients develop further extracolonic intestinal manifestations such as duodenal, or rather papillary adenoma (over 50%), that can also be considered precancerous. There is an increased lifetime risk of developing other carcinomas, especially pancreatic cancer, papilliary thyroid cancer and heptoblastoma.  A characteristic hypertrophy of the retinal pigment epithelium and fundic gland cysts can be found in a large portion of FAP patients. Desmoid tumors can be found intraabdominally, especially in the area of surgical scars or in the mesentery.

In most cases a clinical differential diagnosis of FAP versus Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is possible by colonoscopy (number and location of polyps). Classic FAP is caused by a germline mutation in the APC tumor suppressor gene on chromosome 5 (5q21-22). Molecular genetic examination can identify a germline mutation in the APC gene in 80-90% of patients with typical FAP. A further, random somatic mutation in intact APC alleles results in a loss of heterozygosity (LOH), leading to a total failure of the APC system in the affected epithelial cells. The APC system has an important role in the Wnt/β signaling pathway. Most (over 80%) of APC mutations are nonsense or frameshift mutations that lead to a functional loss of one APC allele, about 9% are splice mutations. In 5-10% of patients there is a deletion or duplication of the APC gene.

Besides classic FAP, there is a milder form called attenuated FAP. These patients develop less than 100 adenomas, which generally develop 10-15 years later than in classic FAP. Moreover, polyps are located more proximally in the colon in comparison to classic FAP.

There are certain genotype-phenotype correlations for typical as well as attenuated FAP.

APC-associated polyposis syndromes include Gardner syndrome (adenomatous polyposis coli as well as soft tissue tumors and osteoma) and Turcot syndrome (adenomatous polyposis coli and CNS tumors, especially Medulloblastoma).

A further polyposis syndrome, MUTYH associated polyposis (MAP) is clinically similar to attenuated FAP. MAP is caused by a germline mutation in the MUTYH gene, and is one of the few tumor syndromes that has autosomal recessive inheritance. The MUTYH gene is involved in the base excision repair (BER). The existence of MAP should be considered when colorectal cancer is diagnosed at a young age, in an individual patient, or in siblings with healthy parents, or in the event of a polyposis syndrome without a mutation in the APC gene. With a positive family history, the index patient must be tested for evidence of a mutation in the APC or MUTYH gene. In the event that a disease causing mutation is found, healthy family members identified as at risk can also be examined (predictive genetic diagnostics). The molecular genetic differentiation of FAP from MAP is important due to risk assessment and precautionary recommendations. Annual colonoscopies should begin at the age of 10 years if an APC mutation is detected, and at 18 years of age if two MUTYH mutations are detected.

In predictive genetic diagnostics, healthy people considered at risk, ideally first degree relatives of the patient, are examined. Every genetic test should have genetic counseling associated with it. For a predictive genetic test, genetic counseling must take place before the test and after presentation of results (Section 2, Paragraph 2 GenDG).