Familial Cancer

, Volume 6, Issue 1, pp 89–95 | Cite as

An association between the 4G polymorphism in the PAI-1 promoter and the development of aggressive fibromatosis (desmoid tumor) in familial adenomatous polyposis patients

  • Catherine F. Li
  • Robert Y. Wei
  • Frank Baliko
  • Bharati Bapat
  • Benjamin A. AlmanEmail author
Original Paper


Aggressive fibromatosis is a mesenchymal neoplasm associated with mutations resulting in β-catenin mediated transcriptional activation. Plasminogen activator inhibitor-1 (PAI-1) is expressed at a high level in aggressive fibromatosis, and using transgenic mice, we found that PAI-1 plays an important role in aggressive fibromatosis tumor formation. Familial adenomatous polyposis is associated with Adenomatous Polyposis Coli gene mutations resulting in β-catenin mediated transcriptional activation, yet only some patients develop aggressive fibromatosis. Since PAI-1 expression is influenced by a promoter 4G/5G polymorphism, we investigated the incidence of this polymorphism in familial adenomatous polyposis patients who did and who did not develop aggressive fibromatosis, as well as sporadic aggressive fibromatosis patients. There was a trend towards association of the 4G allele (associated with high PAI-1 expression) with the development of aggressive fibromatosis in familial adenomatous polyposis patients (50% vs. 19%, P = 0.1). In familial adenomatous polyposis patients who did not develop aggressive fibromatosis, there was a significantly lower proportion of patients with a 4G allele compared to the healthy control (19% vs. 51%, P = 0.0286). The lower incidence of 4G polymorphism in the PAI-1 promoter may be preventive against the development of aggressive fibromatosis. This data provides additional evidence supporting an important role for PAI-1 in the pathogenesis of aggressive fibromatosis.


4G/5G polymorphism Aggressive fibromatosis Familial adenomatous polyposis Plasminogen activator inhibitor-1 



The healthy control genomic DNA samples were kindly supplied by Dr. Steven Gallinger, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada. Derek Stephens provided assistance in the statistical analysis of our data. Thanks also go to members of sequencing facility at The Hospital for Sick Children, University of Toronto for sequencing the PCR products to verify the genotype of the samples. This study was funded by Grants from the National Cancer Institute of Canada to BAA and BAA is supported by the Canadian Research Chairs Program. CFL is a recipient of Ontario Graduate Scholarship.


  1. 1.
    Groden J, Thliveris A, Samowitz W, et al (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600PubMedCrossRefGoogle Scholar
  2. 2.
    Kinzler KW, Nilbert MC, Su LK, et al (1991) Identification of FAP locus genes from chromosome 5q21. Science 253(5020):661–665PubMedCrossRefGoogle Scholar
  3. 3.
    Dormans JP, Spiegel D, Meyer J, et al (2001) Fibromatoses in childhood: the desmoid/fibromatosis complex. Med Pediatr Oncol 37:126–131PubMedCrossRefGoogle Scholar
  4. 4.
    Alman BA, Pajerski ME, Diaz-Cano S, et al (1997) Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder. Diag Mol Pathol 6(2):98–101CrossRefGoogle Scholar
  5. 5.
    Scott RJ, Froggatt NJ, Trembath RC, et al (1996) Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3′ APC gene mutation. Hum Mol Genet 5(12):1921–1924PubMedCrossRefGoogle Scholar
  6. 6.
    Alman BA, Li C, Pajerski ME (1997) Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol 151(2):329–334PubMedGoogle Scholar
  7. 7.
    Tejpar S, Li C, Yu C, et al (2001) Tcf-3 expression and beta-catenin mediated transcriptional activation in aggressive fibromatosis (desmoid tumour). Br J Cancer 85:98–101PubMedCrossRefGoogle Scholar
  8. 8.
    Tejpar S, Nollet F, Li C, et al (1999) Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene 18(47):6615–6620PubMedCrossRefGoogle Scholar
  9. 9.
    Miller JR, Hocking AM, Brown JD, et al (1999) Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18:7860–7872PubMedCrossRefGoogle Scholar
  10. 10.
    Roose J, Clevers H (1999) TCF transcription factors: molecular switches in carcinogenesis. Biochim Biophys Acta 1424:M23-M37PubMedGoogle Scholar
  11. 11.
    Cheon SS, Cheah AY, Turley S, et al (2002) beta-Catenin stabilization dysregulates mesenchymal cell proliferation, motility, and invasiveness and causes aggressive fibromatosis and hyperplastic cutaneous wounds. Proc Natl Acad Sci U S A 99(10):6973–6978PubMedCrossRefGoogle Scholar
  12. 12.
    Bertario L, Russo A, Sala P, et al (2001) Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 95(2):102–107PubMedCrossRefGoogle Scholar
  13. 13.
    Bertario L, Russo A, Sala P, et al (2003) Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis. J Clin Oncol 21(9):1698–1707PubMedCrossRefGoogle Scholar
  14. 14.
    Nugent KP, Phillips RK, Hodgson SV, et al (1994) Phenotypic expression in familial adenomatous polyposis: partial prediction by mutation analysis. Gut 35(11):1622–1623PubMedGoogle Scholar
  15. 15.
    Davies DR, Armstrong JG, Thakker N, et al (1995) Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet 57(5):1151–1158PubMedGoogle Scholar
  16. 16.
    Gebert JF, Dupon C, Kadmon M, et al (1999) Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli. Ann Surg 229(3):350–361PubMedCrossRefGoogle Scholar
  17. 17.
    Caspari R, Olschwang S, Friedl W, et al (1995) Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. Hum Mol Genet 4(3):337–340PubMedCrossRefGoogle Scholar
  18. 18.
    Eccles DM, van der Luijt R, Breukel C, et al (1996) Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene. Am J Hum Genet 59(6):1193–1201PubMedGoogle Scholar
  19. 19.
    Gardner RJ, Kool D, Edkins E, et al (1997) The clinical correlates of a 3’ truncating mutation (codons 1982–1983) in the adenomatous polyposis coli gene. Gastroenterology 113(1):326–331PubMedCrossRefGoogle Scholar
  20. 20.
    Couture J, Mitri A, Lagace R, et al (2000) A germline mutation at the extreme 3’ end of the APC gene results in a severe desmoid phenotype and is associated with overexpression of beta-catenin in the desmoid tumor. Clin Genet 57(3):205–212PubMedCrossRefGoogle Scholar
  21. 21.
    Fodde R, Khan P (1995) Genotype-phenotype correlations at the adenomatous polyposis coli (APC) gene. Crit Rev Oncog 6:291–303PubMedGoogle Scholar
  22. 22.
    Houlston R, Crabtree M, Phillips R, et al (2001) Explaining differences in the severity of familial adenomatous polyposis and the search for modifier genes. Gut 48(1):1–5PubMedCrossRefGoogle Scholar
  23. 23.
    Li CF, Kandel C, Baliko F, et al (2005) Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor). Oncogene 24(9):1615–1624CrossRefGoogle Scholar
  24. 24.
    Preissner KT, May AE, Wohn KD, et al (1997) Molecular crosstalk between adhesion receptors and proteolytic cascades in vascular remodelling. Thromb Haemost 78(1):88–95PubMedGoogle Scholar
  25. 25.
    Nykjaer A, Conese M, Christensen EI, et al (1997) Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 16(10):2610–2620PubMedCrossRefGoogle Scholar
  26. 26.
    Kwaan HC, Wang J, Svoboda K, et al (2000) Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 82(10):1702–1708PubMedCrossRefGoogle Scholar
  27. 27.
    Bajou K, Noel A, Gerard RD, et al (1998) Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4(8):923–928PubMedCrossRefGoogle Scholar
  28. 28.
    Rakic JM, Maillard C, Jost M, et al (2003) Role of plasminogen activator-plasmin system in tumor angiogenesis. Cell Mol Life Sci 60(3):463–473PubMedCrossRefGoogle Scholar
  29. 29.
    Descheemaeker KA, Wyns S, Nelles L, et al (1992) Interaction of AP-1-, AP-2-, and Sp1-like proteins with two distinct sites in the upstream regulatory region of the plasminogen activator inhibitor-1 gene mediates the phorbol 12-myristate 13-acetate response. J Biol Chem 267:15086–15091PubMedGoogle Scholar
  30. 30.
    Kunz C, Pebler S, Otte J, et al (1995) Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53. Nucleic Acids Res 23:3710–3717PubMedCrossRefGoogle Scholar
  31. 31.
    Dennler S, Itoh S, Vivien D, et al (1998) Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 17(11):3091–3100 PubMedCrossRefGoogle Scholar
  32. 32.
    Eriksson P, Kallin B, van ‘t Hooft FM, et al (1995) Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 92(6):1851–1855PubMedCrossRefGoogle Scholar
  33. 33.
    Henry M, Chomiki N, Scarabin PY, et al (1997) Five frequent polymorphrism of the PAI-1 gene. Lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 17:851–858PubMedGoogle Scholar
  34. 34.
    Diamanti-Kandarakis E, Palioniko G, Alexandraki K, et al (2004) The prevalence of 4G5G polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene in polycystic ovarian syndrome and its association with plasma PAI-1 levels. Eur J Endocrinol 150(6):793–798PubMedCrossRefGoogle Scholar
  35. 35.
    Tassies D, Espinosa G, Munoz-Rodriguez FJ, et al (2000) The 4G/5G polymorphism of the type 1 plasminogen activator inhibitor gene and thrombosis in patients with antiphospholipid syndrome. Arthritis Rheum 43(10):2349–2358PubMedCrossRefGoogle Scholar
  36. 36.
    Menges T, Hermans PW, Little SG, et al (2001) Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 357(9262):1096–1097PubMedCrossRefGoogle Scholar
  37. 37.
    Alvarez-Millan JJ, Bocos C, Ferrin V, et al (2002) PAI-1 promoter polymorphism modulates uPA-PAI complex accumulation by breast cancer cells. Oncology 62(3):286–290PubMedCrossRefGoogle Scholar
  38. 38.
    Loktionov A, Watson MA, Stebbings WS, et al (2003) Plasminogen activator inhibitor-1 gene polymorphism and colorectal cancer risk and prognosis. Cancer Lett 189(2):189–196PubMedCrossRefGoogle Scholar
  39. 39.
    Balta G, Altay C, Gurgey A (2003) Prevalence of PAI-1 gene 4G/5G genotype in Azerbaijan and Kyrgyzstan populations: literature review. J Thromb Haemost 1(4):858–859PubMedCrossRefGoogle Scholar
  40. 40.
    Ghadirian P, Liu G, Gallinger S, Schmocker B, Paradis AJ, Lal G, Brunet JS, Foulkes WD, Narod SA (2002). Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer 97(6):807–810PubMedCrossRefGoogle Scholar
  41. 41.
    Soravia C, Berk T, Madlensky L, et al (1998) Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62:1290–1301PubMedCrossRefGoogle Scholar
  42. 42.
    Margaglione M, Grandone E, Cappucci G, et al (1997) An alternative method for PAI-1 promoter polymorphism (4G/5G) typing. Thromb Haemost 77(3):605–606PubMedGoogle Scholar
  43. 43.
    Agresti A (1996) An introduction to categorical data analysis. John Wiley and Sons, Inc., New YorkGoogle Scholar
  44. 44.
    Berrueta L, Kraeft SK, Tirnauer JS, et al (1998) The adenomatous polyposis coli-binding protein EB1 is associated with cytoplasmic and spindle microtubules. Proc Natl Acad Sci U S A 95(18):10596–10601PubMedCrossRefGoogle Scholar
  45. 45.
    Morrison EE, Wardleworth BN, Askham JM, et al (1998) EB1, a protein which interacts with the APC tumour suppressor, is associated with the microtubule cytoskeleton throughout the cell cycle. Oncogene 17(26):3471–3477PubMedCrossRefGoogle Scholar
  46. 46.
    Juwana JP, Henderikx P, Mischo A, et al (1999) EB/RP gene family encodes tubulin binding proteins. Int J Cancer 81(2):275–284PubMedCrossRefGoogle Scholar
  47. 47.
    Baeg GH, Matsumine A, Kuroda T, et al (1995) The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. EMBO J 14(22):5618–5625PubMedGoogle Scholar
  48. 48.
    Ishidate T, Matsumine A, Toyoshima K, et al (2000) The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase. Oncogene 19(3):365–372PubMedCrossRefGoogle Scholar
  49. 49.
    Sturt NJ, Gallagher MC, Bassett P, et al (2004) Evidence for genetic predisposition to desmoid tumours in familial adenomatous polyposis independent of the germline APC mutation. Gut 53(12):1832–1836PubMedCrossRefGoogle Scholar
  50. 50.
    Dietrich WF, Lander ES, Smith JS, et al (1993) Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75(4):631–639PubMedCrossRefGoogle Scholar
  51. 51.
    Halberg RB, Katzung DS, Hoff PD, et al (2000) Tumorigenesis in the multiple intestinal neoplasia mouse: redundancy of negative regulators and specificity of modifiers. Proc Natl Acad Sci U S A 97(7):3461–3466PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • Catherine F. Li
    • 1
  • Robert Y. Wei
    • 1
  • Frank Baliko
    • 1
  • Bharati Bapat
    • 2
  • Benjamin A. Alman
    • 1
    • 3
    Email author
  1. 1.Program in Developmental Biology, The Hospital for Sick Children and University of TorontoTorontoCanada
  2. 2.Samuel Lunenfeld Research InstituteTorontoCanada
  3. 3.The Department of Surgery and Division of Orthopaedic SurgeryThe Hospital for Sick Children and University of TorontoTorontoCanada

Personalised recommendations