Familial Adenomatous Polyposis (FAP)

Familial adenomatous polyposis is an inherited syndrome in which germline alteration of the APC tumor-suppressor gene causes the development of hundreds to thousands of colorectal adenomas, usually beginning in adolescence or early adulthood. Without intervention, the cumulative number of polyps makes progression to colorectal cancer effectively inevitable, which makes FAP a defining example of hereditary cancer predisposition.

Definition

Familial adenomatous polyposis is an autosomal dominant syndrome, caused by germline pathogenic variants in the APC gene, characterized by the development of numerous (classically more than a hundred) colorectal adenomatous polyps and a very high lifetime risk of colorectal cancer.

Scope

This topic covers the genetic basis, characteristic clinical features, and extracolonic manifestations of FAP, and explains why it is managed within hereditary cancer programs. It is a reference overview and does not provide individualized surveillance schedules, surgical advice, or treatment instructions.

Key concepts

• APC gene and autosomal dominant inheritance
• Classic versus attenuated FAP
• Profuse colorectal adenomatous polyposis
• Extracolonic features (duodenal adenomas, desmoid tumors, CHRPE, osteomas)
• Gardner and Turcot syndrome variants
• Genetic testing and family cascade evaluation

Key theories

Two-hit tumor-suppressor model at the APC locus

FAP arises when an inherited inactivating variant in the APC tumor-suppressor gene is followed by somatic loss of the second allele, initiating adenoma formation; APC is also the gatekeeper commonly altered early in sporadic colorectal tumorigenesis.

Mechanisms

The syndrome is driven by germline inactivation of one APC allele in every cell; somatic loss of the remaining functional allele in colonic epithelial cells then removes APC's gatekeeper control, initiating adenoma formation across the colon and rectum. Because APC inactivation is also an early and common event in sporadic colorectal cancer, FAP both causes a severe polyposis phenotype and illuminates the broader genetics of colorectal tumorigenesis. The number and early onset of polyps mean that, without management, one or more will progress to cancer.

Clinical relevance

FAP is managed within hereditary cancer and gastroenterology programs because of its near-certain colorectal cancer risk and its extracolonic features such as duodenal adenomas and desmoid tumors. This entry describes the syndrome as reference material; it is not a source of individualized surveillance, surgical, or treatment recommendations, which require specialist evaluation.

Epidemiology

FAP is rare relative to sporadic colorectal cancer and accounts for a small fraction of all colorectal cancers, but it is one of the more recognizable hereditary syndromes. Cases may be inherited from an affected parent or arise from new germline variants, and an attenuated form with fewer polyps and later onset is also recognized.

Evidence & guidelines

The identification of APC at chromosome 5q21 established the molecular basis of the syndrome, and professional bodies such as the American College of Gastroenterology and collaborating UK societies publish guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes including FAP. These describe evidence and consensus rather than directing the care of any individual.

History

Familial clustering of profuse colonic polyposis was described well before its molecular cause was known. The cloning of the APC gene on chromosome 5q21 in 1991 identified the responsible tumor-suppressor and connected the syndrome to the broader genetic model of colorectal tumorigenesis, transforming FAP into a paradigm of hereditary cancer and enabling genetic testing and family cascade evaluation.

Key figures

• Kenneth Kinzler
• Bert Vogelstein
• Yusuke Nakamura
• Francis Giardiello

Seminal works

• kinzler-1991
• fearon-vogelstein-1990

Frequently asked questions

What causes familial adenomatous polyposis?

It is caused by germline pathogenic variants in the APC tumor-suppressor gene, inherited in an autosomal dominant pattern, which lead to the development of numerous colorectal adenomatous polyps.

How does FAP differ from sporadic colorectal cancer?

FAP is a defined inherited syndrome producing hundreds to thousands of polyps from a young age with a very high lifetime cancer risk, whereas sporadic colorectal cancer typically arises from a small number of acquired polyps later in life; both share early APC inactivation.