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...
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Chapter 079. Cancer Genetics (Part 4) Chapter 079. Cancer Genetics (Part 4) Familial adenomatous polyposis (FAP) is a dominantly inherited coloncancer syndrome due to germline mutations in the adenomatous polyposis coli(APC) tumor-suppressor gene on chromosome 5. Patients with this syndromedevelop hundreds to thousands of adenomas in the colon. Each of these adenomashas lost the normal remaining allele of APC but has not yet accumulated therequired additional mutations to generate fully malignant cells (Fig. 79-2).However, out of these thousands of benign adenomas, several will invariablyacquire further abnormalities and a subset will even develop into fully malignantcancers. 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 functionof the APC protein is still not completely understood but likely providesdifferentiation and apoptotic cues to colonic cells as they migrate up the crypts.Defects in this process may lead to abnormal accumulation of cells that shouldnormally undergo apoptosis and slough off. Figure 79-4 Germline and somatic mutations in the tumor-suppressor geneAPC. APC encodes a 2843-amino-acid protein with 6 major domains: anoligomerization region (O), armadillo repeats (ARM), 15-amino-acid repeats (15AA), 20-amino-acid repeats (20 AA), a basic region, and a domain involved inbinding EB1 and the Drosophila discs large homologue (E/D). Shown are thepositions within the APC gene of a total of 650 somatic and 826 germlinemutations (from the APC database at http://p53.free.fr). The vast majority of thesemutations result in the truncation of the APC protein. Germline mutations arefound to be relatively evenly distributed up to codon 1600 except for 2 mutationhotspots at amino acids 1061 and 1309, which together account for one-third ofthe mutations found in familial adenomatous polyposis (FAP) families. SomaticAPC mutations in colon tumors cluster in an area of the gene known as themutation cluster region (MCR). The location of the MCR suggests that the 20-amino-acid domain plays a crucial role in tumor suppression. Note that loss of thesecond functional APC allele in tumors from FAP families often occurs throughloss of heterozygosity. In contrast to FAP, patients with hereditary nonpolyposis colon cancer(HNPCC, or Lynch syndrome) do not develop multiple polyposis but insteaddevelop only one or a small number of adenomas that rapidly progress to cancer.HNPCC is commonly defined by family history, with at least three individualsover at least two generations developing colon or endometrial cancer, and with atleast one individual diagnosed before the age of 50. Most HNPCC is due tomutations in one of four DNA mismatch repair genes (Table 79-1), which arecomponents of a repair system that is normally responsible for correcting errors infreshly replicated DNA. Germline mutations in MSH2 and MLH1 account for>60% of HNPCC cases, while mutations in MSH6 and PMS2 are much lessfrequent. When a somatic mutation inactivates the remaining wild-type allele of amismatch repair gene, the cell develops a hypermutable phenotype characterizedby profound genomic instability, especially for the short repeated sequences calledmicrosatellites. This microsatellite instability (MIN) favors the development ofcancer by increasing the rate of mutations in many genes, including oncogenes andtumor-suppressor genes (Fig. 79-2). These genes can thus be consideredcaretakers. Figure 79-5 shows an example of the instability in allele sizes fordinucleotide repeats in the cancers of HNPCC patients. Figure 79-5 Demonstration of microsatellite instability in normal and tumor tissuefrom hereditary nonpolyposis colon cancer (HNPCC) patients. In each case thelane marked T contains DNA from a tumor, and the lane marked N contains DNAfrom normal tissue of the same patient. The marker (D2S123, located onchromosome 2) is a microsatellite composed of a tandem repeat of thedinucleotide CA, which varies in length from chromosome to chromosome.Normally, however, the length of the repeat is stable in somatic tissues. In thisexample, a polymerase chain reaction analysis has been applied to genomic DNA,and new alleles for the marker are apparent in tumors 1, 2, 5, and 7. Because thetumor tissue is defective in DNA mismatch repair, clonal abnormalities in copyingof the CA repeat have arisen. Errors are also occurring in functional genes,eventually resulting in the malignant phenotype. (From LA Aaltonen et al, Cluesto the pathogenesis of familial colorectal cancer. Science 260:812, 1993, withpermission; Copyright 1993 AAAS.)