Familial Adenomatous Polyposis - Diagnosis

Diagnosis

Making the diagnosis of FAP before the development of colon cancer is important not just for the individual, but also for the sake of other family members who may be affected. Colonoscopy is considered the diagnostic test of choice as it can provide not only a quantification of polyps throughout the colon but also a histologic diagnosis. Barium enema and virtual colonoscopy can suggest the diagnosis of FAP.

Once the diagnosis of FAP is made, close colonoscopic surveillance with polypectomy is required. Prophylactic colectomy is indicated if more than a hundred polyps are present, if there are severely dysplastic polyps, or if multiple polyps larger than 1 cm are present. When a partial colectomy is performed, colonoscopic surveillance of the remaining colon is necessary as the individual still carries significant risk of developing colon cancer.

Ultrasound of the abdomen and blood tests evaluating liver function are often performed to rule out metastasis to the liver.

Genetic testing provides the ultimate diagnosis in 95% of cases; genetic counseling is usually needed in families where FAP has been diagnosed. Testing may also aid in the diagnosis of borderline cases in families that are otherwise known to p34.3 and p32.1 (1p34.3-p32.1).

APC is a tumour suppressor gene, acting as a "gatekeeper" to prevent development of tumours. Mutation of APC also occurs commonly in incident cases of colorectal carcinoma, emphasizing its importance in this form of cancer.

Although the polyps are inherently benign, the first step of the two-hit hypothesis has already taken place: the inherited APC mutation. Often, the remaining "normal" allele is mutated or deleted, accelerating generation of polyps. Further mutations (e.g. in p53 or kRAS) to APC-mutated cells are much more likely to lead to cancer than they would in non-mutated epithelial cells.

The normal function of the APC gene product is still being investigated; it is present both the cell nucleus and the membrane. The canonical tumor-suppressor function of Apc is suppression of the oncogenic protein beta-catenin. However, other tumor-suppressor functions of Apc may be related to cell adherence and cytoskeleton organization.

MUTYH encodes DNA repair enzyme MYH glycosylase. During normal cellular activities, guanine sometimes becomes altered by oxygen, which causes it to pair with adenine instead of cytosine. MYH glycosylase fixes these mistakes by base excision repair, such that mutations do not accumulate in the DNA and lead to tumor formation. When MYH glycosylase does not function correctly, DNA errors may accrue to initiate tumorigenesis with a clinical presentation similar to that in patients with Apc mutations.