ACTA FAC. MED. NAISS. 2003; 20 (3): 157-161

Review article

GENETICS OF POLYPOSIS SYNDROMES
 

Aleksandar Nagorni, Vuka Katić, Jovica Milanović, Vesna Živković, Goran Bjelaković, Biljana Radovanović-Dinić Clinic for Gastroenterology and Hepatology and Clinic for Pathology Faculty of Medicine Niš
 

INTRODUCTION
Colorectal carcinoma (CRC) is one of the most common malignancies found in Western countries. In 2003 in the United States 150 000 new cases of CRC, were estimated but 50 to 60 thousands people died from CRC (1). Sporadic CRC account for approximately 80-85% of all new diagnoses (2). Familial colorectal cancer (the hereditary nonpolyposis colorectal cancer-HNPCC and inherited polyposis syndromes) account for 10-15% of new cases (3-5).
The inherited gastrointestinal polyposis syndromes account for approximately 1% of all CRC cases (6). They can be divided into adenomatous and hamartomatous syndromes. Adenomatous polyposis syndrome is familial adenomatous polyposis (FAP) with three phenotypic variant of FAP: Gardner's syndrome, Turcot's syndrome and attenuated FAP. Hamartomatous polyposis syndromes are Peutz-Jeghers syndrome, Juvenile polyposis, Cowden's syndrome and Bannayan-Riley-Ruvalacaba syndrome. FAP accounts for about 1% of cases, and the inherited hamartomatous polyposis syndromes account for fewer than 0.1% of cases (3-5).
Cronkhite-Canada syndrome is noninherited gastrointestinal hamartomatous polyposis syndrome with a significant risk of malignancy (7).

FAP
The phenotypic features of FAP and their association with CRC have been showing for more than 100 years (8). FAP is autosomal dominant disorder with an incidence ranging from 1/5000 to 1/17000 (3,9) with penetration rate over 90% (10). Affected patients develop 100-5000 adenomas (mean number more than one thousand) of tubular structure, mostly less than 1 cm in diameter, located in all large bowel segments (3). One or more adenomas inevitably progress to CRC unless they undergo prophylactic colectomy. Most patients with FAP will develop hundreds of adenomas by the age of 16. Untreated patients will acquire CRC at mean age of 39 and die by the age of 42 years (11). By the age of 40 over 90% of CRC in FAP patients are diagnosed (3).
Numerous extracolonic manifestations characterized FAP: intraabdominal desmoids, epidermoid cysts, multiple osteomas, fibromas of the skin, CNS tumors, dental abnormalities, osteodistrophy, congenital hypertrophy of retinal pigment epithelium-CHRPE (12-16). Stomach and duodenal polyps are frequent (17). Duodenal and periampullar carcinoma as well as gallbladder and biliary tract malignancies are observed in some patients with FAP (18-20).
FAP is caused by a germ line mutation of tumor suppressor gene so called APC (Adenomatous Polyposis Coli) gene located on the long arm of chromosome 5 in position 5q21-22 (21-23). APC gene is a multifunctional protein included in processes of transduction, apoptosis, regulation of cell cycle and cell adhesion (16). In most patients APC mutation is located in 5' segment of gene. Mutations toward 3' APC gene segment are rare (24). The gene has 8532 base pairs, 15 coding exons, and a protein product of 2844 amino acid residues (21,22,24,25). All mutations of APC gene detected to date result in truncations of protein (26,27). In recent literature over 400 APC mutations have been described, with 20% confined to two mutational hot spots in exon 15 (2). Mutations of APC gene lead to disruption of APC gene ability to inhibit the function of ß-catenin (28). It is considered that APC gene normally binds to ß-catenin promoting its degradation, thereby preventing activation of growth promoting genes by a ß-catenin/Tcf-4 transcription complex (2).
The disease phenotype is determined by the specific location of a mutation (25,29). Marked phenotypic variability can exist even when members of the same family or unrelated families carry an identical mutation in the APC gene. Identical mutations may produce classic FAP, a completely normal phenotype, or a spectrum of disease between (30,31).
The site of mutation correlated with the degree of polyposis. Mutations of APC between codons 450 and 1600 are associated with more than 100 existing colorectal adenomas, especially mutations between codons 1250 and 1330 (25). An attenuated variant of FAP (attenuated adenomatous polyposis coli-AAPC) is characterized by mutations at either of tge gene, proximal to codon 158 or distal to codon 1900 (24). A late onset of FAP and phenotype of AAPC is characterized by mutations in exons 3 and 4 (32) in the splice sites of intron 3 in the extreme 5' region of the gene (33,34). Deletion of 5 pair of base at codon 1309 (exon 15) cause development of colorectal adenoma in young age, but patients died from CRC 10 years earlier than patients with the other mutations (35). Mutations in APC gene between codons 1445 and 1578 are associated with severe desmoids, osteomas, epidermoid cysts and polyps of the upper gastrointestinal tract. CHRPE is present in FAP patients in whom the mutation lies downstream to exon 9, but nor in individuals with mutations upstream of this exon. Mutations beyond codon 16000 are associated with AAPC and different number of extracolonic manifestations (2,12). It is impossible to detect APC mutation in 20-50% of patients-APC negative FAP, suggesting influence of different genetic factors.
The mutation status determines the choice of surgical procedure. Subtotal colectomy with ileo-rectal anastomosis is primary therapeutic choice in FAP patients with mutations proximal to codon 1250, but in patients with mutations distal to codon 1250 a total colectomy with ileal pouch should be done (12).
 

PEUTZ JEGHERS SYNDROME
In 1921 Peutz originally described this syndrome. In 1949 Jeghers et al. reported in detail about the syndrome. Jeghers noted an association among oral mucocutaneous pigmentation, intestinal polyposis and an increased risk of invasive carcinoma (2).
Peutz-Jeghers syndrome is an inherited autosomal dominant disorder (2,36) with an incidence of probably about 1 per 100000-120000 newborns. The specific genetic mutation leading to this condition (LKB1) has been localized on the short arm of chromosome 19, 19p 13.3 (37). The affected gene codes for a serine/threonine kinase protein-LKB1 (37-39). Mutations in LKB1 gene result in a truncated protein product and the loss of kinase activity. The formation of the hamartomas in Peutz-Jeghers syndrome are result of germline mutations in the LKB1 gene (37,40,41). Subsequent somatuic mutations of LKB1 and others leads to loss of heterozygosity and the transformation of hamartomas into adenomas and then carcinomas (40,42,43).
Although Peuth-Jeghers syndrome is hamartomatous polyposis syndrome, glandular polyps-adenomas and carcinomas have been associated with the syndrome (2).

JUVENILE POLYPOSIS
Juvenile polyposis syndrome is an autosomal dominant condition affecting 1 in 100000 people. The syndrome is described for the first time by McColl in 1964. The syndrome is characterized by the development of hamartomatous polyps an increased risk of gastrointestinal malignancy (44,45). The genetic defect leading to this condition has been localized to chromosome 18q21 (46). In 50% of familial cases the responsible gene is SMAD-4 gene which encodes a cytoplasmatic mediator of the transforming growth factor-beta signal transduction pathway (47,48). In other familial and sporadic cases, the responsible genetic mutation has yet to be identified.
 

COWDEN'S SYNDROME
Cowden's syndrome is rare autosomal dominant disorder with almost complete penetrance (2). The syndrome is characterized by hamartomatous polyposis syndrome with characteristic dermatologic manifestations. Except skin lesions, intestinal polyps, thyroid disease and breast disease are diagnosed (49).
Genetic defect is on chromosome 10q23 and involves the gene that codes for protein tyrosine phosphatase and tensin homolog - PTEN (50,51).
 

BANNAYAN-RILEY-RUVALACABA SYNDROME
It is inherited autosomal dominant syndrome with proved mutations in the pTEN gene on chromosome 10q23. This syndrome occurs as a result of an allelic variation of Cowden's syndrome (51,52). The syndrome causes an intestinal hamartomatous polyposis syndrome associated with characteristic dermatologic lesions. The dermatologic lesions include lentigines of the penis and vulva, verrucae, acanthosis nigricans, and hyperpigmentations of the skin of the penis (53).
Up to 45% of patients will have intestinal polyps. The polyps are limited to the distal ileum and colon. Malignant transformation of the polyps has not been identified in these patients (2).
 

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