Familial adenomatous polyposis (FAP) is a dominantly inherited colon cancer syndrome due to germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene on chromosome 5. Patients with this syndrome develop hundreds to thousands of adenomas in the colon. Each of these adenomas has lost the normal remaining allele of APC but has not yet accumulated the required additional mutations to generate fully malignant cells (Fig. 79-2). However, out of these thousands of benign adenomas, several will invariably acquire further abnormalities and a subset will even develop into fully malignant cancers. APC is thus considered to be a gatekeeper. | Chapter 079. Cancer Genetics Part 4 Familial adenomatous polyposis FAP is a dominantly inherited colon cancer syndrome due to germline mutations in the adenomatous polyposis coli APC tumor-suppressor gene on chromosome 5. Patients with this syndrome develop hundreds to thousands of adenomas in the colon. Each of these adenomas has lost the normal remaining allele of APC but has not yet accumulated the required additional mutations to generate fully malignant cells Fig. 79-2 . However out of these thousands of benign adenomas several will invariably acquire further abnormalities and a subset will even develop into fully malignant cancers. APC is thus considered to be a gatekeeper for colon tumorigenesis Fig. 79-4 shows germline and somatic mutations found in the APC gene. The function of the APC protein is still not completely understood but likely provides differentiation and apoptotic cues to colonic cells as they migrate up the crypts. Defects in this process may lead to abnormal accumulation of cells that should normally undergo apoptosis and slough off. Figure 79-4 Germline and somatic mutations in the tumor-suppressor gene APC. APC encodes a 2843-amino-acid protein with 6 major domains an oligomerization region O armadillo repeats ARM 15-amino-acid repeats 15 AA 20-amino-acid repeats 20 AA a basic region and a domain involved in binding EB1 and the Drosophila discs large homologue E D . Shown are the positions within the APC gene of a total of 650 somatic and 826 germline mutations from the APC database at http . The vast majority of these mutations result in the truncation of the APC protein. Germline mutations are found to be relatively evenly distributed up to codon 1600 except for 2 mutation hotspots at amino acids 1061 and 1309 which together account for one-third of the mutations found in familial adenomatous polyposis FAP families. Somatic APC mutations in colon tumors cluster in an area of the gene known as the mutation cluster region MCR .
