Familial adenomatous polyposis (FAP) accounts for about 1% of all colon tumours (1). The frequency of the incidence of this disease 1 in 8000 to 1 in 10 000 births (2). The age of manifestation of symptoms in patients varies considerably and it even varies between siblings. However, it can be assumed that the occurrence of the colon tumour at a young age should be a signal to perform family anamnesis, which allows to identify whether this is a hereditary predisposition (3). The occurrence of a single case of the disease does not exclude a high hereditary predisposition since a given patient may be the first to carry the mutation. FAP symptoms occur earlier than those of HNPCC (Hereditary Non-polyposis Colorectal Cancer) and appear in the second decade of life. However, cases have been observed of the occurrence of the disease as early as five years of age, and in our group there was one three-year old patient to have polyps diagnosed (4). The genetic basis of the occurrence of adenomatous polyps is the presence of mutations in the APC genes in cases of FAP patients and in the MUTYH gene in the cases of the recessive form of colon polyposis.
The suppressor tumour genes are involved in the control of cell proliferation. Protein products of suppressor genes take part in the control of the cell cycle as its inhibitors and are also components of system for contact inhibition of cell-growth. The suppressor genes perform the function in maintaining the number of cells at a constant level. Disturbances in these mechanisms lead to an increase of the frequency of cell divisions as well as to an increase of the number of errors during division. This leads to accumulation of alterations in the genetic material and selection of an immortal clone of very frequent cell divisions, which is capable of residing in other tissues.
In the case of suppressor genes the phenotype of mutation is masked by an appropriate allele of the gene. In the initiation of the tumour o process/tumourigenesis two independent mutations occur within the locus of the suppressor gene (2). In the case of the carrier state of the mutated allele of the APC gene the risk of occurrence of the second mutation, and thus of initiation of tumour disease is very high.
FAP was recognized as a heritable pathogenic syndrome already in the 1920s. In 1972 Gardner syndrome was described, which is a form of FAP characterized not only by the presence of hundreds or even thousands of polyps in the intestine, but also of osteomas and retinal hypertrophy (Congenital Hypertrophy of the Retinal Pigment Epithelium – CHRPE). The occurrence of FAP was associated with the q21-q22 region of chromosome 5 on the basis of a large deletion discovered during cytogenetic analysis as well as research results from the linkages of RFLP markers in a patient with Gardner syndrome and with an advanced polyp growth in the colon (5). At the end of the 1980s studies of associations revealed a region on the long arm of chromosome 5, which encompassed the APC and MCC genes, which are distant from one another by 150 kbp. In 1991, the following three genes were studied in FAP patients: DP1, SRP19 and DP2.5. These genes were found in the region which underwent deletion. In four unrelated FAP patients four mutations were found in the DP2.5 (now known as the APC gene) leading to the Stop codon from which one was transmitted to offspring (1). In the following year 79 FAP patients were examined and in 67% of them mutations in the APC gene were observed. In the study, 92% of the mutations were those which resulted in the truncation of the protein product of the APC gene (6). In many countries, investigations were undertaken to research the occurrence of mutations in the APC gene and a database was established in which 826 inherited mutations and 650 somatic mutations were collected (7). The APC gene protein function has been studied since 1993 when it was observed that it binds to β-catenin, which indicated participation in cell adhesion (8).
Very interesting is the observation of differential splicing as a result of which exon 14 and exon 15, which encompasses almost 70% of the APC gene are excised, and the fragment that remains binds with the 3’ end of the SRP1 gene. Excision of exon 14 or 15 leads to the development of two isoforms differing from each other by their ability of binding microtubules and β-catenin as well as by the sequence of 3’ region which does not undergo translation and which can exert an influence on the stability of mRNA and the function of the product (23). In this case alternative splicing of the gene is associated with the regulation of the APC protein activity and suggests that it fulfils many different functions in the cell, especially, that in the alternative splicing of the protein over 75% of exons take part.
The full-length APC protein contains 2843 amino acids and can be found in the cytoplasm and in cell nucleus (1, 20). So far several proteins have been identified to interact with the APC protein. These are DLG protein, microtubule protein, GSKβ-3, β-catenin, γ-catenin, p34, Tid56, Auxin protein. Interactions with many proteins indicate that the APC protein participates in the regulation of many cell processes including: cell division, migration, adhesion and cell fate determination (24). In the APC protein several functional domains have been identified. The base domain encompasses amino acids 2200-2400 (24). The 5’ end of the protein, between amino acids 1-171, is involved in oligomerization. In the APC protein there are two β-catenin binding sites – in the fragment comprising three 15-nucleotide repeats between amino acids 1020-1169 and in the region of 20 amino acid repeats between amino acids 1324-2075. Binding with microtubules, which occurs with increased gene expression, takes place by means of the fragment encompassing amino acids 2130-2483. Amino acids 2560-2843 are the site of binding with the EB1 protein, while amino acids 2771-2843 bind with the DLG protein (1). The region associated with the process of apoptosis has not been distinguished, although it was observed that expression of the appropriate APC protein in the intestinal neoplastic cell line leads to the occurrence of this phenomenon. A product of the APC gene of 300 kDa mass participates in the inhibition of cell growth in the mucous cells of the colon.
Both proteins bind with a cell adhesion protein E-cadherin. Fearon proposed a model in which the APC protein participates in signal transduction and through degradation of β-catenin affects the activity of T-cell transcription factor 4 (25). The protein that regulates the formation of the APC protein and β-catenin complex is protein kinase ZW3/GSK3β. Phosphorylation of the APC protein activates β-catenin binding. The activity of the GSK3β kinase is regulated by the DSH protein, which interacts with the protein product of the WNT1 gene. The APC protein is bound with ZW3/GSK3β kinase and is capable of inhibiting the transcription induced by β-catenin. In case of the loss of the function of the APC product the transcription factor Tcf4 (TCF7L2) is activated. The cell is stimulated to proliferate as a result of activation of the c-MYC gene transcription by Tcf4 (26). The product of the c-MYC gene resides in the cell nucleus and is capable of binding with DNA, activating the growth gene – ornithine decarboxylase (ODC1) and the CDC25A gene. It is also an inhibitor of the GAS1 gene. It was also shown that the activated β-catenin-Tcf4 complex induces Tcf1 expression (27). In the mucous cells of the colon the APC is a negative regulator of the cell cycle through the regulation of β-catenin level, which is activated by the proliferation signal derived from the transmembrane protein E-cadherin. In case of the loss of functionality of this gene the balance between cell division and cell apoptosis becomes disturbed.
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