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The complex genotype–phenotype relationship in familial adenomatous polyposis

Järvinen, Heikki Ja; Peltomäki, Päivib

European Journal of Gastroenterology & Hepatology: January 2004 - Volume 16 - Issue 1 - p 5-8
Leading articles

The severity of polyposis and occurrence of extracolonic manifestations are associated with the site of truncating mutations of the APC gene.

Severe polyposis occurs in patients with the mutation in the mutation cluster region (codons 1250–1400) and, for example, osteomas, dental changes and desmoid tumours most commonly in patients with mutations beyond codon 1400 (−1580).

Besides predictive genetic testing knowledge of the APC gene mutation offers only a limited clinical application in the treatment of familial adenomatous polyposis.

Familial adenomatous polyposis predisposes to colorectal cancer through multiple colorectal adenomas. The age of onset of adenomas and their number vary between families affected by this dominantly inherited trait, even within families. The same applies to a variety of associated manifestations including epidermoid cysts, osteomas, dental anomalies, desmoid tumours, retinal pigmentation and upper gastrointestinal polyps. The phenotype variation has a relationship with the site of truncating mutations on the APC gene. Thus, mutations at the mutation cluster region (codons 1250–1400) tend to cause early onset and severe polyposis whereas osteomas, dental changes and desmoids are most frequent in patients with the mutation 3′ to codon 1400. The correlation observed, however, seems quite complex. Explanations may include variable interference of different mutant APC proteins on the wild-type APC function. There is also evidence suggesting an effect of modifier genes. The clinical applications of genotype–phenotype correlation on the management of patients with familial adenomatous polyposis remain limited apart from predictive genetic testing.

aDepartment of Gastroenterological Surgery, Helsinki University Central Hospital, Helsinki, Finland; and bDepartment of Medical Genetics, University of Helsinki, Helsinki, Finland.

Correspondence to Prof. H.J. Järvinen, Department of Gastroenterological Surgery, Helsinki University Central Hospital, P.O. Box 340, FIN-00029 HUS, Helsinki, Finland. Tel: +358 9 471 72320; fax +358 9 471 76046; e-mail:

Received 12 August 2003

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Familial adenomatous polyposis (FAP) is an autosomal dominant inherited cancer predisposition syndrome classically characterized by at least 100 adenomatous polyps of the colon and rectum [1].

It is caused by a germline mutation in the adenomatous polyposis coli (APC) gene located on the long arm of chromosome 5 (5q 21-22). The phenotype of the disease is quite variable regarding the time of the appearance and number of colonic adenomas. While in most affected families more than 100 adenomas develop in patients between the ages of 10 and 20 years, in some families the onset is later, up to 40 years or more, and the number of adenomas may be fewer than 100. This kind of mild disease is called attenuated FAP (AFAP). Further variability follows from the occurrence of many extracolonic manifestations, such as epidermoid cysts, osteomas, dental anomalies and desmoid tumours, which were first noted in the 1950s by Eldon J. Gardner. His observations were based on patients from the Utah ‘Kindred 109’ and are the reason why the eponym ‘Gardner's syndrome’ is used for FAP patients with similar extracolonic symptoms [2]. More recently, even more extracolonic manifestations associated with FAP have been identified, such as congenital hypertrophy of the retinal pigment epithelium (CHRPE), fundic gland polyps of the stomach, duodenal adenomas and carcinoma, and some more rare tumour types (hepatoblastoma, medulloblastoma, papillary thyroid carcinoma) [1].

A definite accumulation of some extracolonic symptoms in some families seems to exist, and patients from other families consistently exhibit a severe form of polyposis. The genetic background behind phenotypic variations between families has remained enigmatic despite much attention during the last 10 years since the discovery of the APC gene and its different mutations.

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Genetic background of FAP

The APC gene was localized to chromosome 5q 21-22 in 1987, and isolated in 1991 [3,4]. The gene extends over a region of 120 kilobases and contains 15 numbered exons (altogether, 21 exons have been identified, including several alternatively spliced exons). The gene product, a protein of 2843 amino acids is supposed to negatively regulate the Wnt signalling pathway. It binds to and causes the degradation of beta-catenin in association with axin/conductin and glycogen synthase kinase 3 beta [5]. Lack of functional APC causes unregulated intracellular accumulation of beta-catenin.

A year ago the Human Genome Mutation Database ( had recorded more than 300 pathogenic APC mutations [6]. Most mutations produce a truncated APC protein of variable length depending on the site of the mutation. The mutations distribute on the whole length of the APC gene but a major part concentrates between codons 1250 and 1400 on exon 15, the central mutation cluster region. The observation of several different mutations in affected FAP families and the great phenotypic variation between families has generated extensive investigation to determine whether or not truncating mutations of the same region result in a similar phenotype.

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Genotype–phenotype relationship

Soon after characterization of the APC gene it was suggested that a truncating mutation between codons 1255 and 1467, roughly corresponding to the mutation cluster region, causes a profuse type of polyposis [7]. This was later confirmed in several studies, and especially mutations at codon 1309 (5 bp deletion) seem to associate with severe early onset polyposis [8–10]. On the other hand, mutations located at each end of the gene, either before codon 168 (at the 5′ end) or 3′ to codon 1580 tend to lead to mild polyposis of late onset [10–12]. Similar attenuated FAP occurs in mutations of the alternatively spliced region of exon 9 [9,13]. Thus, the site of APC mutation has no linear correlation with the number of adenomas, but the association is more complex as shown; for example, in a recent analysis from the St. Mark's Polyposis Registry series of patients with classical FAP [14]. Adenoma counts were highest (mean 3459 polyps) in the mutation cluster region (codons 1250–1400) and lowest (mean 550 polyps) in patients with the mutation in the post-beta-catenin binding region (codons 1169–1250); mutations within the pre-armadillo region (codons 168–453) and 3′ to the mutation cluster region (codons 1400–1580) were associated with moderate polyposis. The issue is further confused by observations of variable adenoma counts in members of the same family or between families with an identical mutation [15,16].

The occurrence of extracolonic manifestations also correlates with mutation site. Typical retinal pigmentation (CHRPE) is almost invariably detectable if the mutation lies between codons 457 and 1444 [17], but not in patients with other mutation sites. Osteomas and desmoid tumours, earlier giving rise to the use of the eponym ‘Gardner's syndrome', are most common in patients with the mutation beyond codon 1403 or 1444, the post-mutation cluster region [6,9,10]. The observation by Oku et al. (see page 101 of this issue of the journal) and previous data by Davies et al. fit well with the assumption that dental anomalies follow the incidence pattern of osteomas and desmoids in relation to mutation site [18,19]. It must be noted, however, that even though desmoid tumours have the highest frequency (60%) in patients with mutation between codons 1445 and 1580, their frequency was still high (20%) if the mutation was 5′ to codon 1444 in the analysis of 269 FAP patients by Friedl et al. [10].

For other extracolonic manifestations the observations about genotype–phenotype relations are less consistent. In one study the majority of cases (80%) with severe duodenal adenomatosis of stage IV or periampullary adenocarcinoma occurred in patients who had the APC mutation 3′ to the codon 1051 (−1556) [20]. One case report also describes advanced duodenal adenomas combined with sparse colonic disease in a family with APC mutation at codon 1520 [21]. However, more extensive studies are needed to explore whether or not there are genotype groups particularly vulnerable to periampullary cancer within FAP patients when almost all eventually develop duodenal adenomas. Similarly, one study observed that the mutations of hepatoblastoma patients of seven FAP kindreds situated between codons 141 and 1230, but no significant difference existed in the mutation site as compared with families with no hepatoblastoma [22].

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Explanations for genotype–phenotype correlation

The observations of varying phenotype according to the site of the germline mutation, as described above, may reflect the involvement of different functional domains of APC [23], although the exact mechanisms remain to be elucidated. Recently, a German group demonstrated that the mutant APC protein truncated at codon 1309 strongly inhibited the wild-type APC activity in beta-catenin/Tcf mediated transcription, while mutant APC gene products associated with less severe polyposis (codons 386 and 1465) interfered only weakly with the wild-type APC activity [24]. This was considered as evidence that certain mutation types lead to enhanced adenoma growth and other similar mechanisms might also exist. Besides reduced ability of the resulting proteins to interfere with the wild-type APC, mutations associated with attenuated polyposis may give rise to milder phenotypes by an alternative mechanism: Heppner Goss et al. [25], showed that attenuated APC alleles are able to produce functional protein from internal initiation of translation. Furthermore, it is well established that tumorigenesis in FAP requires biallelic inactivation of the APC gene consistent with Knudson's two-hit hypothesis [26], and interdependence of the first and second hits may explain some genotype–phenotype correlations [27]. Possible modifier genes, which have been demonstrated to act in the Min mouse model of polyposis [28], and to some extent also in FAP patients [14], may offer additional explanations for the variance of phenotype.

In this context it should be noted that in some 5–33% of FAP kindreds the APC mutation has escaped identification. While it is possible that the methods of identification have been defective in some series, it remains possible that there will be new FAP gene loci to be found. A proportion of FAP-like solitary cases of polyposis was newly shown to be explained by mutations of MYH gene, a new recessively inherited trait presenting as either few multiple adenomas or attenuated FAP [29].

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Clinical implications

The most important clinical issue in FAP is the progression of colorectal adenomas to carcinoma. This can be prevented by prophylactic colectomy at the age of 20–25 years at the latest. Preservation of the rectum leaves a significant rectal cancer risk in the long term, which can be minimized using restorative proctocolectomy with ileal pouch–anal anastomosis instead of ileorectal anastomosis. As restorative proctocolectomy involves more risk of poor anal function attempts have been made to find groups with a high risk for rectal cancer on the basis of genotype, and offer ileorectal anastomosis for low-risk patients. Vasen et al. observed that the cumulative rectal excision rate was 2.7 times higher in patients with the APC mutation 3′ to codon 1250 than in patients 5′ to that codon [30]. The division of FAP patients into two groups only has proved to be too simple, as presented before. At present, ileorectal anastomosis is recommended mainly for attenuated FAP alone [31]. In very mild polyposis polypectomies with chemoprevention (e.g., sulindac) may be considered [32]. Such decisions, however, should be based more on the endoscopic and histological features rather than on the genotype, especially as the genotype of AFAP is poorly defined.

The two other important clinical problems in FAP are desmoid tumours and duodenal adenomas with the consequent risk of periampullary carcinoma. Even though the genotype may predict different risk groups for desmoids there are no real preventive measures to be applied. Because surgery is a known risk factor for desmoids, postponing prophylactic surgery may be advisable in families with a family history of desmoids or with a vulnerable genotype but not if colonic polyposis is profuse [10]. Otherwise genotype offers little help in clinical decisions apart from predictive genetic testing, which is very helpful in the early diagnosis of FAP [9,33].

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familial adenomatous polyposis; genotype–phenotype correlation; colorectal cancer predisposition; adenomatous polyposis coli gene; genetic testing

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