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.
1. Groden J, Thliveris A, Samowitz W et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 1991; 66: 589-600.
2. Bisgaard ML, Fenger K, Bulow S et al.: Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum Mutat 1994; 3: 121-125.
3. Al-Tassan N, Eisen T, Maynard J et al.: Inherited variants in MYH are unlikely to contribute to the risk of lung carcinoma. Hum Genet 2003; 114: 207-210.
4. Distante S, Nasioulas S, Somers GR et al.: Familial adenomatous polyposis in a 5 year old child: a clinical, pathological, and molecular genetic study. J Med Genet 1996; 33: 157-160.
5. Borun P, Bartkowiak A, Banasiewicz T et al.: High Resolution Melting analysis as a rapid and efficient method of screening for small mutations in the STK11 gene in patients with Peutz-Jeghers syndrome. BMC medical genetics 2013; 14: 58.
6. Miyoshi Y, Nagase H, Ando H et al.: Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1992; 1: 229-233.
7. Brozek I, Plawski A, Podralska M et al.: Thyroid cancer in two siblings with FAP syndrome and APC mutation. International journal of colorectal disease 2008; 23: 331-332.
8. Rubinfeld B, Souza B, Albert I et al.: Association of the APC gene product with beta-catenin. Science 1993; 262: 1731-1734.
9. Pawlak A, Plawski A, Smoczkiewicz P et al.: Familial polyposis coli – inducing mutations in APC gene in Poland. J Appl Genet 1977; 38: 77-85.
10. Plawski A, Podralska M, Slomski R: DNA bank for Polish patients with predispositions to occurrence of colorectal polyposis. Hereditary Cancer in Clinical Practice 2011; 9 (suppl. 2).
11. Borun P, Kubaszewski L, Banasiewicz T et al.: Comparativehigh resolution melting: a novel method of simultaneous screening for small mutations and copy number variations. Hum Genet 2014; 133: 535-545.
12. Dymerska D, Serrano-Fernandez P, Suchy J et al.: Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch syndrome and FAP patients. The Journal of molecular diagnostics: JMD 2010; 12: 82-90.
13. Plawski A, Banasiewicz T, Borun P et al.: Familial adenomatous polyposis of the colon. Hered Cancer Clin Pract 2013; 11: 15.
14. Plawski A, Lubinski J, Banasiewicz T et al.: Novel germline mutations in the adenomatous polyposis coli gene in Polish families with familial adenomatous polyposis. Journal of medical genetics 2004; 41: e11.
15. Plawski A, Nowakowska D, Podralska M et al.: The AAPC case, with an early onset of colorectal cancer. International journal of colorectal disease 2007; 22: 449-451.
16. Plawski A, Podralska M, Slomski R: Recurrent APC gene mutations in Polish FAP families. Hereditary cancer in clinical practice 2007; 5: 195-198.
17. Plawski A, Slomski R: APC gene mutations causing familial adenomatous polyposis in Polish patients. J Appl Genet 2008; 49: 407-414.
18. Stec R, Plawski A, Synowiec A et al.: Colorectal cancer in the course of familial adenomatous polyposis syndrome („de novo” pathogenic mutation of APC gene): case report, review of the literature and genetic commentary. Archives of medical science: AMS 2010; 6: 283-287.
19. Santoro IM, Groden J: Alternative splicing of the APC gene and its association with terminal differentiation. Cancer Res 1997; 57: 488-494.
20. Kinzler KW, Nilbert MC, Su LK et al.: Identification of FAP locus genes from chromosome 5q21. Science 1991; 253: 661-665.
21. Lambertz S, Ballhausen WG: Identification of an alternative 5’ untranslated region of the adenomatous polyposis coli gene. Hum Genet 1993; 90: 650-652.
22. Samowitz WS, Thliveris A, Spirio LN et al.: Alternatively spliced adenomatous polyposis coli (APC) gene transcripts that delete exons mutated in attenuated APC. Cancer Res 1995; 55: 3732-3734.
23. Sulekova Z, Reina-Sanchez J, Ballhausen WG: Multiple APC messenger RNA isoforms encoding exon 15 short open reading frames are expressed in the context of a novel exon 10A-derived sequence. Int J Cancer 1995; 63: 435-441.
24. Al-Tassan N, Chmiel NH, Maynard J et al.: Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet 2002; 30: 227-232.
25. Fearon ER: Human cancer syndromes: clues to the origin and nature of cancer. Science 1997; 278: 1043-1050.
26. He TC, Sparks AB, Rago C et al.: Identification of c-MYC as a target of the APC pathway. Science 1998; 281: 1509-1512.
27. Roose J, Huls G, van Beest M et al.: Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 1999; 285: 1923-1926.
28. Stenson PD, Ball EV, Mort M et al.: Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 2003; 21: 577-581.
29. Domizio P, Talbot IC, Spigelman AD et al.: Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients. J Clin Pathol 1990; 43: 738-743.
30. Mandl M, Paffenholz R, Friedl W et al.: Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis. Hum Mol Genet 1994; 3: 181-184.
31. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990; 61: 759-767.
32. Morin PJ: Beta-catenin signaling and cancer. Bioessays 1999; 21: 1021-1030.
33. Slupska MM, Baikalov C, Luther WM et al.: Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J Bacteriol 1996; 178: 3885-3892.
34. Jones S, Emmerson P, Maynard J et al.: Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. Hum Mol Genet 2002; 11: 2961-2967.
35. Sieber OM, Lipton L, Crabtree M et al.: Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348: 791-799.
36. Joslyn G, Carlson M, Thliveris A et al.: Identification of deletion mutations and three new genes at the familial polyposis locus. Cell 1991; 66: 601-613.
37. Kinzler KW, Nilbert MC, Vogelstein B et al.: Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 1991; 251: 1366-1370.
38. Gardner E: Discovery of the Gardner syndrome. Birth Defects Orig Art Ser 1972; 2: 48-51.
39. Cetta F, Dhamo A: Inherited multitumoral syndromes including colorectal carcinoma. Surg Oncol 2007; 16 (suppl. 1): S17-23.
40. Nieuwenhuis MH, Vasen HF: Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 2007; 61: 153-161.
41. Cheadle JP, Sampson JR: Exposing the MYtH about base excision repair and human inherited disease. Hum Mol Genet 2003; 12 (spec. No 2): R159-165.
42. Sampson JR, Dolwani S, Jones S et al.: Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 2003; 362: 39-41.
43. Cruz-Correa M, Giardiello FM: Familial adenomatous polyposis. Gastrointest Endosc 2003; 58: 885-894.
44. Krush AJ, Traboulsi EI, Offerhaus JA et al.: Hepatoblastoma, pigmented ocular fundus lesions and jaw lesions in Gardner syndrome. Am J Med Genet 1988; 29: 323-332.
45. Giardiello FM, Yang VW, Hylind LM et al.: Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 2002; 346: 1054-1059.
46. Giardiello FM, Hamilton SR, Krush AJ et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328: 1313-1316.
47. Cohen M, Thomson M, Taylor C et al.: Colonic and duodenal flat adenomas in children with classical familial adenomatous polyposis. Int J Surg Pathol 2006; 14: 133-140.
48. Caspari R, Friedl W, Boker T et al.: Predictive diagnosis in familial adenomatous polyposis: evaluation of molecular genetic and ophthalmologic methods. Z Gastroenterol 1993; 31: 646-652.
49. Wallis YL, Macdonald F, Hulten M et al.: Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis. Hum Genet 1994; 94: 543-548.
50. Kashiwagi H, Kanazawa K, Koizumi M et al.: Development of duodenal cancer in a patient with familial adenomatous polyposis. J Gastroenterol 2000; 35: 856-860.
51. Farrington SM, Tenesa A, Barnetson R et al.: Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 2005; 77: 112-119.
52. Sarre RG, Frost AG, Jagelman DG et al.: Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps. Gut 1987; 28: 306-314.
53. Zwick A, Munir M, Ryan CK et al.: Gastric adenocarcinoma and dysplasia in fundic gland polyps of a patient with attenuated adenomatous polyposis coli. Gastroenterology 1997; 113: 659-663.
54. Heiskanen I, Kellokumpu I, Jarvinen H: Management of duodenal adenomas in 98 patients with familial adenomatous polyposis. Endoscopy 1999; 31: 412-416.
55. Jones IT, Jagelman DG, Fazio VW et al.: Desmoid tumors in familial polyposis coli. Ann Surg 1986; 204: 94-97.
56. Klemmer S, Pascoe L, DeCosse J: Occurrence of desmoids in patients with familial adenomatous polyposis of the colon. Am J Med Genet 1987; 28: 385-392.
57. Bell B, Mazzaferri EL: Familial adenomatous polyposis (Gardner’s syndrome) and thyroid carcinoma. A case report and review of the literature. Dig Dis Sci 1993; 38: 185-190.
58. Camiel MR, Mule JE, Alexander LL et al.: Thyroid carcinoma with Gardner’s syndrome. N Engl J Med 1968; 279: 326.
59. Itoh H, Ohsato K: Turcot syndrome and its characteristic colonic manifestations. Dis Colon Rectum 1985; 28: 399-402.
60. Itoh H, Ohsato K, Yao T et al.: Turcot’s syndrome and its mode of inheritance. Gut 1979; 20: 414-419.
61. Paraf F, Jothy S, Van Meir EG: Brain tumor-polyposis syndrome: two genetic diseases? J Clin Oncol 1997; 15: 2744-2758.
62. Van Meir EG: „Turcot’s syndrome”: phenotype of brain tumors, survival and mode of inheritance. Int J Cancer 1998; 75: 162-164.
63. Giardiello FM, Petersen GM, Brensinger JD et al.: Hepatoblastoma and APC gene mutation in familial adenomatous polyposis. Gut 1996; 39: 867-869.
64. Gruner BA, DeNapoli TS, Andrews W et al.: Hepatocellular carcinoma in children associated with Gardner syndrome or familial adenomatous polyposis. J Pediatr Hematol Oncol 1998; 20: 274-278.
65. Krawczuk-Rybak M, Jakubiuk-Tomaszuk A, Skiba E et al.: Hepatoblastoma in a 3-month-old infant with APC gene mutation – case report. J Pediatr Gastroenterol Nutr 2011 Aug 23.
66. Soravia C, Berk T, Madlensky L et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 1998; 62: 1290-1301.
67. Barnetson RA, Devlin L, Miller J et al.: Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin Genet 2007; 72: 551-555.
68. Nielsen M, Hes FJ, Nagengast FM et al.: Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin Genet 2007; 71: 427-433.
69. Oshima M, Dinchuk JE, Kargman SL et al.: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 1996; 87: 803-809.
70. Chiu CH, McEntee MF, Whelan J: Sulindac causes rapid regression of preexisting tumors in Min/+ mice independent of prostaglandin biosynthesis. Cancer Res 1997; 57: 4267-4273.
