Original article| Volume 143, ISSUE 2, P89-98, February 2004

Gene expression in aggressive fibromatosis

  • Keith M Skubitz
    Reprint requests: Keith M. Skubitz, MD, Box 286, University Hospital, Minneapolis, MN 55455, USA.
    Departments ofDepartment of Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA

    the Masonic Cancer Center, Minneapolis, Minnesota, USA
    Search for articles by this author
  • Amy P.N Skubitz
    Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
    Search for articles by this author


      Aggressive fibromatosis represents a group of tumors with heterogeneous patterns of biologic behavior. In this study, gene expression in 12 samples of aggressive fibromatosis, as well as that in samples of normal skeletal muscle and a variety of normal tissues, was determined at Gene Logic Inc (Gaithersburg, MD), with the use of Affymetrix GeneChip U_133 arrays containing approximately 33,000 genes. Gene-expression analysis was performed with the Gene Logic Gene Express® software system. Differences in gene expression were quantified as the fold change in gene expression between the sets of fibromatosis tissue and normal skeletal muscle. A set of genes was then identified that was significantly overexpressed in aggressive fibromatosis compared with expression in normal muscle. This set of genes was then further examined for expression in a variety of normal tissues. We identified genes that were selectively overexpressed in aggressive fibromatosis compared with expression in 448 samples comprising 16 different nonneoplastic tissues. In particular, ADAM12, WISP-1, SOX-11, and fibroblast activation protein-α were uniquely overexpressed in aggressive fibromatosis compared with expression in normal tissues. In addition, the technique of Eisen clustering identified 2 distinct subgroups of aggressive fibromatosis with regard to gene expression. We conclude that gene-expression patterns may be useful in the further classification of subtypes of aggressive fibromatosis and that such classification could have clinical significance.


      ADAM (a disintegrin and metalloproteinase), AF (aggressive fibromatosis), APC (adenomatous polyposis coli), FAP (fibroblast activation protein), HMG (high-mobility group), IGF (insulin-like growth factor), IGFBP (insulin-like growth factor–binding protein), MFH (malignant fibrous histiocytoma), MMTV (mouse mammary-tumor virus), NOS (not otherwise specified), PDGF (platelet-derived growth factor), TGF (transforming growth factor), TNF (tumor necrosis factor)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Alman BA, Pajerski ME, Diaz-Cano S, Corboy K, Wolfe HJ. Aggressive fibromatosis (desmoid tumor) is a monoclonal disorder. Diagn Mol Pathol 1997;6:98–101

      2. Alman BA, Goldberg MJ, Naber SP, Galanopoulous T, Antoniades HN, Wolfe HJ. Aggressive fibromatosis. J Pediatr Orthop 1992;12:1–10

      3. Bertario L, Russo A, Sala P, Eboli M, Giarola M, D’Amico F, et al. Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis. Int J Cancer 2001;95:102–7

      4. Li M, Cordon-Cardo C, Gerald WL, Rosai J. Desmoid fibromatosis is a clonal process. Hum Pathol 1996; 27:939–43

      5. Lucas DR, Shroyer KR, McCarthy PJ, Markham NE, Fujita M, Enomoto TE. Desmoid tumor is a clonal cellular proliferation: PCR amplification of HUMARA for analysis of patterns of X-chromosome inactivation. Am J Surg Pathol 1997;21:306–11

        • Middleton S.B.
        • Frayling I.M.
        • Phillips R.K.
        Desmoids in familial adenomatous polyposis are monoclonal proliferations.
        Br J Cancer. 2000; 82: 827-832
      6. Hoos A, Lewis JJ, Antonescu CR, Dudas ME, Leon L, Woodruff JM, et al. Characterization of molecular abnormalities in human fibroblastic neoplasms: a model for genotype-phenotype association in soft tissue tumors. Cancer Res 2001;61:3171–5

      7. Bus PJ, Verspaget HW, van Krieken JH, de Roos A, Keizer HJ, Bemelman WA, et al. Treatment of mesenteric desmoid tumours with the anti-oestrogenic agent toremifene: case histories and an overview of the literature. Eur J Gastroenterol Hepatol 1999;11:1179–83

      8. Lewis JJ, Boland PJ, Leung DH, Woodruff JM, Brennan MF. The enigma of desmoid tumors. Ann Surg 1999; 229:866–72; discussion 872–3

      9. Smith AJ, Lewis JJ, Merchant NB, Leung DH, Woodruff JM, Brennan MF. Surgical management of intra-abdominal desmoid tumours. Br J Surg 2000;87:608–13

      10. Alman BA, Li C, Pajerski ME, Diaz-Cano S, Wolfe HJ. Increased beta-catenin protein and somatic APC mutations in sporadic aggressive fibromatoses (desmoid tumors). Am J Pathol 1997;151: 29–34

        • Eastman Q.
        • Grosschedl R.
        Regulation of LEF-1/TCF transcription factors by Wnt and other signals.
        Curr Opin Cell Biol. 1999; 11: 233-240
      11. Cheon SS, Cheah AY, Turley S, Nadesan P, Poon R, Clevers H, et al. 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 2002;99:6973–8

      12. Alman BA, Greel DA, Ruby LK, Goldberg MJ, Wolfe HJ. Regulation of proliferation and platelet-derived growth factor expression in palmar fibromatosis (Dupuytren contracture) by mechanical strain. J Orthop Res 1996;14:722–8

      13. Magro G, Lanteri E, Micali G, Paravizzini G, Travali S, Lanzafame S. Myofibroblasts of palmar fibromatosis co-express transforming growth factor-alpha and epidermal growth factor receptor. J Pathol 1997;181:213–7

      14. de Andrade CR, Cotrin P, Graner E, Almeida OP, Sauk JJ, Coletta RD. Transforming growth factor-beta1 autocrine stimulation regulates fibroblast proliferation in hereditary gingival fibromatosis. J Periodontol 2001;72:1726–33

      15. Skubitz KM, Cheng E, Clohisy D, Manivel C, Thompson R, Skubitz APN. Differential gene expression in liposarcoma, lipoma and adipose tissue. Manuscript submitted for publication

      16. Gilpin BJ, Loechel F, Mattei MG, Engvall E, Albrechtsen R, Wewer UM. A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo. J Biol Chem 1998;273:157–66

      17. Galliano MF, Huet C, Frygelius J, Polgren A, Wewer UM, Engvall E. Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha-actinin-2, is required for myoblast fusion. J Biol Chem 2000;275:13933–9

      18. Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem 2000;275:18574–80

      19. McKusick VA. Online Mendelian Inheritance in Man. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD); 2000. Available at:

      20. Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, et al. WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci U S A 1998;95:14717–22

      21. Lovell-Badge R, Hacker A. The molecular genetics of Sry and its role in mammalian sex determination. Philos Trans R Soc Lond B Biol Sci 1995;350:205–14

      22. Jay P, Goze C, Marsollier C, Taviaux S, Hardelin JP, Koopman P, et al. The human SOX11 gene: cloning, chromosomal assignment and tissue expression. Genomics 1995;29:541–5

      23. Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci U S A 1994;91:5657–61

      24. Pineiro-Sanchez ML, Goldstein LA, Dodt J, Howard L, Yeh Y, Chen WT. Identification of the 170-kDa melanoma membrane–bound gelatinase (seprase) as a serine integral membrane protease. J Biol Chem 1997;272:7595–601

      25. Goldstein LA, Ghersi G, Pineiro-Sanchez ML, Salamone M, Yeh Y, Flessate D, et al. Molecular cloning of seprase: a serine integral membrane protease from human melanoma. Biochim Biophys Acta 1997;1361:11–9

      26. Couture J, Mitri A, Lagace R, Smits R, Berk T, Bouchard HL, et al. 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 2000;57:205–12

      27. Saito T, Oda Y, Kawaguchi K, Tanaka K, Matsuda S, Tamiya S, et al. Possible association between higher beta-catenin mRNA expression and mutated beta-catenin in sporadic desmoid tumors: real-time semiquantitative assay by TaqMan polymerase chain reaction. Lab Invest 2002;82:97–103

      28. Shitoh K, Konishi F, Iijima T, Ohdaira T, Sakai K, Kanazawa K, et al. A novel case of a sporadic desmoid tumour with mutation of the beta catenin gene. J Clin Pathol 1999;52:695–6

      29. Tejpar S, Nollet F, Li C, Wunder JS, Michils G, dal Cin P, et al. Predominance of beta-catenin mutations and beta-catenin dysregulation in sporadic aggressive fibromatosis (desmoid tumor). Oncogene 1999;18:6615–20

      30. Saito T, Oda Y, Tanaka K, Matsuda S, Tamiya S, Iwamoto Y, et al. Beta-catenin nuclear expression correlates with cyclin D1 overexpression in sporadic desmoid tumours. J Pathol 2001;195:222–8

      31. Abraham SC, Reynolds C, Lee JH, Montgomery EA, Baisden BL, Krasinskas AM, et al. Fibromatosis of the breast and mutations involving the APC/beta-catenin pathway. Hum Pathol 2002;33:39–46

      32. Rubinfeld B, Souza B, Albert I, Muller O, Chamberlain SH, Masiarz FR, et al. Association of the APC gene product with beta-catenin. Science 1993;262:1731–4

        • Polakis P.
        Wnt signaling and cancer.
        Genes Dev. 2000; 14: 1837-1851
      33. Munemitsu S, Albert I, Souza B, Rubinfeld B, Polakis P. Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci U S A 1995;92:3046–50

      34. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, et al. Activation of beta-catenin–Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997;275:1787–90

      35. Batelle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 2002;111:251–63

      36. Hiraoka A, Sugimura A, Seki T, Nagasawa T, Ohta N, Shimonishi M, et al. Cloning, expression and characterization of a cDNA encoding a novel human growth factor for primitive hematopoietic progenitor cells. Proc Natl Acad Sci U S A 1997;94:7577–82

      37. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, et al. Identification of heregulin, a specific activator of p185erbB2. Science 1992;256:1205–10

      38. Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, et al. Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses. Neuron 2000;26:443–55

      39. Wolpowitz D, Mason TB, Dietrich P, Mendelsohn M, Talmage DA, Role LW. Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron 2000;25:79–91

      40. Fernandez PA, Tang DG, Cheng L, Prochiantz A, Mudge AW, Raff MC. Evidence that axon-derived neuregulin promotes oligodendrocyte survival in the developing rat optic nerve. Neuron 2000;28:81–90

        • Berglund E.O.
        • Ranscht B.
        Molecular cloning and in situ localization of the human contactin gene (CNTN1) on chromosome 12q11-q12.
        Genomics. 1994; 21: 571-582
      41. Berglund EO, Murai KK, Fredette B, Sekerkova G, Marturano B, Weber L, et al. Ataxia and abnormal cerebellar microorganization in mice with ablated contactin gene expression. Neuron 1999;24:739–50