Rev. gastroenterol. Perú v.22 n.2 Lima abr./jun. 2002
TRABAJOS DE REVISIÓN
Adenomatous Polyposis Coli Gene as a Gatekeeper
Takamori Nakayama (1); Tetsuo Morishita (2); Toshiaki Kamiya (3)
(1) Department of Surgery, Shizuoka Red Cross Hospital 8-2. Ohtemachi, Shizuoka-shi, Shizuoka, 420-0853 Japan
(2) Department of Internal Medicine, Tokyo Dental College. 5-11-13, Sugano Ichikawa-shi, Chiba, 272-8513 Japan
(3) Department of Gastroenterology, School of Medicine, Christiann University of Bolivia
El Gen de la Poliposis Coli Adenomatosa (APC), es un gen supresor tumoral que se encuentra en el cromosoma 5q21. Tiene una secuencia de 2843 aminoácidos con un peso de 312 kD. La mutación de este gen APC ocurre en los estadíos tempranos de la mayoría de cánceres colo-rectales esporádicos; y hasta en un 30% de las poliposis adenomatosas familiares. La falta del APC determinará una migración inadecuada de las células mucosas del colon y su acumulación para la formación de pólipos; lo que marca una etapa en la carcinogénesis.
Un estudio adecuado en grupos predispuestos puede llevar a la quimioprevención y/o tratamiento precoz de estos pólipos.
Palabras clave: Poliposis colónica, lesiones preneoplásicas.
The Adenomatous Polyposis Coli (APC) Gene is a tumor suppressor gene located in the chromosome 5q21. It has a sequence of 2843 amino acids and a weight of 312 kD. The mutation of the APC gene occurs at the early stages of most sporadic colorectal cancers; and up to 30% in familial adenomatous polyposis. The absence of APC will indicate the inadequate migration of colon mucous cells and its accumulation resulting in polyps formation, which determines a stage in carcinogenicity.
An adequate study in prone groups may lead to chemoprophylaxis and/or early treatment of polyps.
Key words: Colonic polyposis, preneoplastic lesions.
The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that functions as a gatekeeper(1, 2). The APC alterations play an important role in the development of tumors during the multistep process of carcinogenesis. An accumulation of somatic mutations facilitates colorectal tumorigenesis from adenomas to carcinomas. Approximately 80% of colorectal cancers correspond to the Vogelstein model (3, 4). The Knudson two-hit model can be applied to the APC in the development of colorectal carcinoma both sporadically and on a hereditary basis. Mutation of one allele is sufficient for the development of adenomas, suggesting a dose-dependent effect by the gene product and/or a dominant-negative effect by its mutated form.
The APC is mutated in sporadic colorectal cancer and in familial adenomatous polyposis (FAP). Specifically, acquired APC mutations initiate the majority of sporadic cancers (5), and inherited APC mutations initiate FAP (2, 6). The APC mutations occur in the early stage of tumor development in the majority of sporadic colorectal cancers (5). Germline mutation (nonsense, frameshift) is frequent, occurring in up to 30 % of FAP patients (7). Disease penetrance is almost 100 % at 40 years of age (8).
Molecular characterization is beneficial in the screening for individuals who may have a hereditary cancer predisposition. The APC testing may provide a useful tool for reducing the cancer incidence and mortality.
ADENOMATOUS POLYPOSIS COLI GENE (APC)
The APC was first identified in 1986 (11) and the exact gene locus was established in 1991 by positional cloning from chromosome 5q 21 (1, 2). The APC has 15 exons and encodes a predicted gene product of 2843 amino acids with a molecular weight of about 312 kD. The most frequent sporadic mutation of the APC is a deletion in codon 1309.
The APC product is involved in the intracellular signaling pathway of E-cadherin (10, 11). E-cadherin interacts to from the adherence junction. The catenins are proteins that bind to the cytoplasmic tails of the E-cadherin protein. Alpha-catenin and beta-catenin bind to the APC product. The APC protein has been shown to associate with microtubules and cell adhesion molecules by modifying transcriptional activation and cell cycle regulation. Alteration in cell-to-cell contact leads to defects in intercellular signaling. Loss of the APC function could impair cell migration, possibly via the stabilization of cell-cell adhesions as increased free cytoplasmic beta-catenin is incorporated into the E-cadherin-catenin unit. A simultaneous increase in cell proliferation could further enhance accumulation of cells at the cryptvillus boundary and result in polyp formation, setting the stage for carcinogenesis (12).
There is no evidence of an association between replication error and the presence of somatic APC mutations (13).
FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
FAP is a inherited, autosomal-dominant cancer-predisposition. The APC mutation is responsible for FAP(6, 7). The disease is classically characterized by the development, usually during the teenege years, of at least 100 adenomatous polyps in the colorectum. Though these polyps are premalignant, ultimate progression to carcinoma is inevitable in the absence of therapeutic intervention (14, 15).
A progressive accumulation of somatic alterations is important in the adenomacarcinoma sequence. The APC alterations are closely associated with the development of dysplastic changes of the colon. APC mutations have been demonstrated in aberrant crypt foci containing only a few dysplastic crypts, but no APC mutations have been found in hyperplastic or normal mucosa.
Adenomatous polyps can develop proximally in the gastrointestinal tract, most notably in the stomach and second part of the duodenum. Periampullary polyps manifest adenomatous changes similar to colorectal adenomas and are likely to progress to periampullary cancer once these changes take place. Among FAP extracolonic manifestations, periampulllary cancer is the leading cause of death in FAP patients (16).
Numerous extraintestinal lesions may cosegregate with adenomatous polyposis. The association of FAP, peritoneal desmoid, and exostoses has been termed Gardner's syndrome (17). The combination of cerebral neoplasia and FAP is known as Turcot's syndrome (18).
Primary prevention of colorectal cancer by dietary or pharmacological interventions is being increasingly viewed as a real possibility for high-risk patients. Several epidemiological and case control studies have been published demonstrating a protective effect of aspirin in subjects at average to moderate risk of adenoma and cancer (19, 20, 21, 22) An ideal model for evaluating adenoma prevention has been studied in FAP, and several have evaluated various agents, including nonsteroidal anti-inflammatory agents (NSAIDs) such as sulindac (23, 24, 25). Another class of agents, selective cyclooxygenase-2 (COX-2) inhibitors, is also being actively investigated (26, 27). The other mode of intervention has been surgical, in the form of prophylactic colectomy.
A single base change of APC I1307K is a novel form of mutagenesis that clearly shows the importance of the genetic background. The missense mutation causes a substitution of lysine for isoleucine at codon 1307 and leads to the formation of (A) 8 instead of the normal (A) 3T (A) 4. This unstable tract apparently increases the rate of somatic mutations in the region between codons 1296 and 1317 in the APC gene tumor DNA is positive for the 1307 allele and manifests somatic mutations in 50 % of patients (28).
The vast mayority (90%) of APC I1307K mutations lead to truncation and inactivation of the APC protein. While the APC I1307K missence mutation does not alter the function of the encoded protein, it has been shown to result in a small hypermutable region of the gene and to facilitate the development at colorectal cancer (28).
APC I1307K AND ASHKENAZIM
Ashkenazi Jews who immigrated from Russia, Poland or Romania to Israel are at the highest risk for colorectal cancer. The Ashkenazis who immigrated to the United States and Australia are also considered high-risk religious-ethnic group for this disease (29, 30). The Ashkenazim population is made up of numerous subgroups with differing geographic backgrounds, so it would not be surprising if there were large variations in the allele frequency among these sub-groups.
Control populations are important to identify potential signals from candidate alleles and discriminate them from the noise generated by sporadic cancers. This is primarily because sistematic mutations in the APC are present in 70% of sporadic colorectal cancers, and germ-line mutations in the APC are infrequents (5).
A missence mutation in APC I1307K is associated with some familial colorectal cancers in Ashkenazi Jews. In one study the APC I1307K mutation was found in 10% (22/211) of Ashkenazi Jews with colorectal cancer, 28% (7/25) of Ashkenazi Jews with a positive family history for colorectal cancer, 6 % (47/766) of Ashkenazi Jews without colorectal cancer, and 0 of 243 non-Ashkenazim (28). This mutation profile differs from that observed for the general population. Although the study was not adequately controlled for known environmental risk factors, these observations may reflect an increased risk of colon cancer among carriers.
On the other hand, the prevalence of the APCI1307K variant was not increased in Ashkenazi women at risk for breast-ovarian cancer or those with ovarian cancer (31).
Nor was it a risk factor for a Norwegian population with familial or sporadic colorectal, or breast cancers (32).
The identifications of individuals at high risk of cancer can offer promising steps for the prevention of cancer. The APC is one of the most frequently mutated genes in colorectal carcinomas. The APC I1307K polymorphism may be a target of increased mutation or only weakly tumorigenic.
Given the uncertainty of the cancer risk assessments and limited availability of genetic counseling, patients considering genetic testing should undergo formal cancer risk counseling. Complex bioethical issues must be considered as well. While a positive test is helpful, a negative test is not safe. Because other genes might involve the carcinogenesis
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