Genetic Aspects in FAP

Familial adenomatous polyposis (FAP) is a hereditary disease characterised by the presence of adeno-matous polyps in the colon and rectum, from a minimum of 100 (necessary number for diagnosis) up to more than 7 000, which are genetically determined by mutations of the APC (adenomatous polyposis coli) gene located on chromosome 5 [3]. Children have a 50% probability of being affected regardless of their sex. The onset is in the second and third decade of life, even if cases of early (13 months of age) or late onset (60 years) are reported. The incidence ranges from 1:8000 to 1:22000 and it is approximately estimated that one out of three patients with FAP does not have a familial history of the disease, as is therefore probably presenting a spontaneous mutation.

FAP is a generalised hyperproliferative disorder due to the constant activation of transcription and growth factors, as an ultimate result of the alterations of the protein codified by the APC gene. In addition to the typical colorectal disease, it presents various extra-colonic manifestations (gastroenteric and others) [4]. APC gene mutations responsible for FAP are of a germinal type, whereas the mutation of the somatic line is present in approximately 80% of the sporadic tumours of the colon-rectum.

From a clinical point of view, simple rectal exploration is often diagnostic: polyps in the ampulla may be evaluated with the exploring finger. Obviously, to observe the distribution, number and morphology of the polyps and to detect possible malignancies, only a complete endoscopic examination allows evaluation of the entire colon and rectum.

The main transcript of the APC gene is a 2843 amino acids protein, which is expressed in several adult tissues. This protein is implicated in signal transmission, negatively regulating the Wnt-1 path through its bind with a E-catenin. The protein altered by the genetic mutation is not capable of binding the E-catenin, which accumulates in the cytoplasm, determining constant activation of transcription and growth factors.

However, the main target of the germinal as well as the somatic mutations is exon 15, as it contains 75% of the codifying sequences of APC. In the majority of FAP patients, frameshift and nonsense germinal mutations were identified, with transcription of a truncated and hypofunctional protein. Germinal mutations are generally uniformly distributed between codons 200 and 1600, rarely above codon 1600. Moreover, they affect codons 1061 and 1309 more frequently. Together these account for one third of all these mutations.

It was demonstrated that the risk of developing specific FAP manifestations, as well as the disease severity on the large bowel, is related to the type of genetic mutation [5-7]. Severe forms of FAP are more frequently observed in mutations between codons 1250 and 1464. This implies an early onset, with symptoms (abdominal pain, diarrhoea, blood in the faeces) even before 20 years of age, a high number (carpet) of polyps in the colon and rectum and an early progression to malignancy.

On the other hand, the attenuated forms of FAP seem to be related to mutations of the 5' and 3' extremities of the gene, or the alternative splicing sites of codon 9. This form, called AFAP (attenuated familial adenomatous polyposis) [8], is characterised by a later onset of symptoms as well as the progression to cancer and by the presence of the so-called flat adenomas, which are mainly located in the right colon with a relative sparing of the rectum.

Mutations of codons 457 and 1444 are characteristic in patients who also present CHRPE, whereas desmoid tumours are limited to those who present mutations of codons 1403 and 1578. These, and other extra-colonic manifestations of FAP (osteomas, epidermal cysts, upper gastroenteric polyposis), can also often be observed in the presence of mutations between codons 1445 and 1578, or between 1395 and 1493.

We must mention that some clinically ascertained forms of FAP do not have a recognisable genetic mutation; that is to say, that these patients are negative for known mutations of the APC gene. These forms are characterised by a particular severity of the disease in the colon-rectum [9]. They present an early onset even with a low number of polyps which have a strong tendency to progress early to cancer, whereas extra-colonic manifestations are less frequent and severe. In these cases, screening of the call-up patients remains the domain of endoscopic examinations at a young age.

Molecular genetic techniques [10] allow individual analysis and, if a known mutation is found, allow certain diagnosis. In this way, the identification of sporadic cases is also possible. The identification of mutations of the codifying region of APC, due to the large size of the gene, is a long and expensive procedure so, in view of the fact that the majority of the mutations leads to the transcription of a truncate protein, it is faster and more convenient to evaluate mutations by means of protein analysis. More than 90% of mutations described to date result in a halt of the protein synthesis, with the expression of a truncate product. Blue White Assay and PTT (protein truncation test) are efficient and rapid methods for identifying truncate proteins.

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