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© Borgis - Postępy Nauk Medycznych 1/2015, s. 25-33
*Andrzej Pławski1, Paweł Boruń1, Marzena Skrzypczak-Zielińska1, Piotr Krokowicz2, Michał Drews2, Jacek Paszkowski3, Jan Lubiński4, Tomasz Banasiewicz3
Rodzinna polipowatość gruczolakowata
Familial adenomatous polyposis of the colon
1Institute of Human Genetics, Polish Academy of Sciences, Poznań
Head of Institute: prof. Jerzy Nowak, MD, PhD
2Department of General and Colorectal Surgery, Poznań University of Medical Sciences
Head of Department: prof. Piotr Krokowicz, MD, PhD
3Department of General, Endocrinological and Gastroenterological Oncology Surgery, Poznań University of Medical Sciences
Head of Department: prof. Michał Drews, MD, PhD
4Department of Genetics and Pathology, International Hereditary Cancer Centre, Pomeranian Medical University, Szczecin
Head of Department: prof. Jan Lubiński, MD, PhD
Streszczenie
Rodzinna polipowatość jelita (FAP) jest dobrze poznanym zespołem predyspozycji do występowania choroby nowotworowej rozwijającej się z licznych polipów okrężnicy i odbytnicy, dziedziczonym w sposób autosomalno-dominujący. Pierwszymi objawami FAP są biegunka i krew w stolcu. Wraz z rozwojem choroby nowotworowej dochodzi do utraty masy ciała i osłabienia organizmu. FAP występuje z częstością 1 na 10 000 urodzeń. Czas wystąpienia polipów i ich liczba są w przypadku tej choroby zróżnicowane. Klasyczna forma FAP charakteryzuje się występowaniem więcej niż 100 polipów, które pojawiają się w drugiej dekadzie życia. Średni wiek występowania polipów to 15 lat. Najmłodszy chory miał 3 lata. Polipy charakteryzują się dużym potencjałem rozwoju w kierunku nowotworu złośliwego, który może wystąpić od późnego dzieciństwa do 70. roku życia. Łagodna forma polipowatości rodzinnej charakteryzuje się łagodniejszym przebiegiem niż klasyczny FAP. Występowanie FAP jest związane z mutacjami w genie supresorowym nowotworów APC, który został opisany w 1991 roku. Gen APC jest zlokalizowany na chromosomie 5q21 i związany z kontrolą proliferacji komórek. Forma recesywna FAP jest spowodowana przez mutacje w genie MUTYH. Gen MUTYH jest zaangażowany w naprawę oksydacyjnych uszkodzeń DNA. Polipowatość związana z MUTYH (MAP) jest skłonnością do występowania polipów jelita, ale liczba polipów jest niższa w klasycznym FAP.
Wysokie ryzyko wystąpienia choroby nowotworowej w tych chorobach sprawia, że należą do ważnych zagadnień medycznych. W Polsce badania molekularne wykonywane są od ponad piętnastu lat. W Instytucie Genetyki Człowieka PAN w Poznaniu utworzono Bank DNA dla polskich pacjentów z polipowatościami. W Banku DNA zgromadzono próbki DNA od siedmiuset rodzin z FAP.
Summary
Familial adenomatous polyposis (FAP) is a well-known predisposition to the occurrence of a large number of polyps in the colon and rectum inherited in an autosomal dominant manner. The first symptoms of FAP are diarrhea and blood in the stool. Weight loss and weaknesses occur after the development of advanced tumour. The incidence of FAP disorder is one per 10 000 newborns. There is a high heterogeneity with regard to the number and timing of occurrence of polyps. The classical form of FAP is characterized by the occurrence of more than 100 polyps, which appear in the second decade of life. The average time of occurrence of polyps is 15 years. The earliest symptoms of polyposis were observed in a three-year-old child. The polyps are characterized by large potential for the development towards malignant tumour. Turning into malignancy can occur from the late childhood to the 70s. Attenuated adenomatous polyposis coli cases are characterized by a benign course of disease as opposed to the classical FAP. The occurrence of FAP is associated with mutations in the APC tumour suppressor gene, which was described in 1991. The APC gene is a tumour suppressor gene located on chromosome 5q21 involved in cell proliferation control. A recessive form of FAP is caused by mutations in the MUTYH gene occurring in both alleles of the gene. The MUTYH gene is involved in repairing the oxidative DNA damage. MUTYH associated polyposis (MAP) is a predisposition to the occurrence of polyps of the colon but the number of polyps is lower in comparison to classical FAP.
The high risk of cancer observed in those syndromes makes them important medical issues. Molecular studies of polyposis of the colon have been performed in Poland for over fifteen years. In 1997 at the Institute of Human Genetics in Poznań, the DNA Bank for Polish FAP patients was established. In the Bank the DNA samples from over six hundred FAP families have been collected so far.



Introduction
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.
History of investigations of the APC gene
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).
In Poland, investigations of the APC gene were started in the middle of 90s of the 20th century, and a DNA Bank of patients was established in 1997 at the Institute of Human Genetics of the Polish Academy of Sciences in Poznań (9). In 2011 the Bank was transformed into a DNA Bank of patients with intestinal polyposis (10). Currently, in the bank there are samples from over 758 families of which 677 are families with FAP, 28 with JPS, 48 with PJS and 5 cases of Cowden syndrome. Molecular studies have allowed to identify mutations in the APC gene in 323 families. 194 types of mutations have been identified of which 147 are deletions, 32 insertions and 115 substitutions. Also methodologies of studies of hereditary predispositions to the occurrence of intestine polyposis have been developed (5, 11-18).
APC structure and APC protein function
The APC gene (adenomatous polyposis coli) is located on chromosome 5 in the q21 region and contains 21 exons (19). The characteristic attribute of the APC gene is the occurrence of a large exon 15, which encompasses over 70% of the coding sequence. The expression of the gene is observed in all tissues. The product of transcription is mRNA of the length of 8538 nucleotides (1, 20). The first exons of the gene may form tissue-specific alternative transcripts (21), e.g. in brain a product of the APC gene occurs for which Start codon is located in exon BS (brain specific). Elimination of codon 1, which encodes the super helix domain, known to serve either homo- or heterodimerization affects the functionality of the protein product (19). Alternative splicing of primary exons of the the gene may be related to the occurrence of the attenuated adenomatous polyposis coli (AAPC) (22). A similar effect was observed in one of the two families with mutations at the 3’ end of exon 9 where, in one case, a modifying effect was shown of alternative splicing leading to a milder FAP phenotype. In this connection it is suggested that the kind, location of mutation as well as the effect of alternative splicing exert an influence on the course of the disease.
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.
Mutations of the APC gene

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otrzymano: 2014-12-10
zaakceptowano do druku: 2015-01-05

Adres do korespondencji:
*Andrzej Pławski
Institute of Human Genetics PAS
ul. Strzeszyńska 32, 60-479 Poznań
tel. +48 (61) 657-92-15
andp@man.poznan.pl

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