Pathway

Familial Adenomatous Polyposis Coli (FAP) is the most prevalent of several related syndromes which carry a strongly enhanced risk for colon cancer (Table 13.1). Related afflictions include Gardners syndrome, Turcots syndrome, and an attenuated form of FAP. These syndromes are distinguished from each other by the kind of tumors and developmental defects that appear in other organs besides the large intestine.

Patients with standard FAP characteristically develop hundreds of adenomatous polyps in their colon, rectum, and duodenum as well as gland polyps in the stomach, early in life. Congenitally, they display hypertrophy of the retinal pigment epithelium. Although the polyps are adenomatous, i.e. benign tumors, eventually one or the other progresses to malignancy and carcinomas develop, typically in the third or fourth decade of life. The life-time risk of carcinoma development approaches 100%. Therefore, removal of the colon is used as a preventive measure (see also 13.6). FAP is inherited in an autosomal-dominant fashion. With its constellation of multiple tumors in the same organ, carcinoma development much before the usual age, and autosomal-dominant mode of inheritance, FAP is a prime example of an inherited tumor disease corresponding to the 'Knudson' model (^5.1).

The gene mutated in FAP was identified in 1991 and was named APC, for 'adenomatous polyposis coli'. Positional cloning (^Box 13.1) in families with FAP and the related Gardner's syndrome was successful, strongly aided by a key patient with a cytogenetically recognizable deletion in chromosome 5q21 where the APC gene resides. APC turned out to be a large gene (Figure 13.2) comprising

Table 13.1. Some hereditary syndromes predisposing to colon cancer

Syndrome

Colon symptoms

Other tumors

Gene affected

Familial

multiple adenomatous

stomach and duodenal

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