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Reduced Fhit protein expression in human malignant mesothelioma

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Abstract

Human malignant mesothelioma (MM) is an aggressive neoplasm related to occupational exposure to asbestos and characterised by a long latency time. Multiple chromosomal deletions and DNA losses have been revealed in MM by studies performed with karyotypic, comparative genomic hybridisation and loss of heterozygosity (LOH) analyses. Among frequently deleted chromosomal sites, LOH at chromosome 3p has been detected in MM, suggesting the presence of one or several tumour suppressor genes that have an important role in development of the disease. The FHIT (fragile histidine triad) tumour suppressor gene, located at 3p14.2, has been proposed to be a target to major human lung carcinogens, such as tobacco smoke and asbestos. Although many studies have indicated decreased Fhit protein expression in a variety of malignancies, there is no report of FHIT gene aberrations or Fhit protein abnormalities in MM. We examined expression of the Fhit protein and LOH at the FHIT gene in malignant mesothelioma. Altogether, 13 paraffin embedded MM tumours were analysed for Fhit protein expression, and 21 fresh tumours and 10 cell cultures for LOH at the FHIT gene with two intragenic microsatellite markers. All tumours showed less intense immunostaining than normal bronchial epithelium or mesothelium. Fhit expression was absent or reduced in 54% (7 of 13) of the tumours, with the weakest staining observed in poorly differentiated areas. Allele loss was seen in 3 of 10 (30%) of the MM cell lines, but only in 1 of the 21 fresh tumours studied, suggesting concealment of LOH by normal cells present in MM tumours. In conclusion, our present data indicate a frequent decrease of Fhit protein expression, thus supporting the significance of FHIT inactivation in development of MM.

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References

  1. Attanoos RL, Gibbs AR (1997) Pathology of malignant mesothelioma. Histopathology 30:403–418

    Google Scholar 

  2. Baffa R, Gomella LG, Vecchione A, Bassi P, Mimori K, Sedor J, Calviello CM, Gardiman M, Minimo C, Strup SE, McCue PA, Kovatich AJ, Pagano F, Huebner K, Croce CM (2000) Loss of FHIT expression in transitional cell carcinoma of the urinary bladder. Am J Pathol 156:419–424

    Google Scholar 

  3. Bianchi AB, Mitsunaga SI, Cheng JQ, Klein WM, Jhanwar SC, Seizinger B, Kley N, Klein-Szanto AJ, Testa JR (1995) High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. Proc Natl Acad Sci U S A 92:10854–10858

    Google Scholar 

  4. Campiglio M, Pekarsky Y, Menard S, Tagliabue E, Pilotti S, Croce CM (1999) FHIT loss of function in human primary breast cancer correlates with advanced stage of the disease. Cancer Res 59:3866–3869

    Google Scholar 

  5. Capuzzi D, Santoro E, Hauck WW, Kovatich AJ, Rosato FE, Baffa R, Huebner K, McCue PA (2000) Fhit expression in gastric adenocarcinoma: correlation with disease stage and survival. Cancer 88:24–34

    Article  CAS  PubMed  Google Scholar 

  6. Chizhikov V, Chikina S, Gasparian A, Zborovskaya I, Steshina E, Ungiadze G, Samsonova M, Chernyaev A, Chuchalin A, Tatosyan A (2002) Molecular follow-up of preneoplastic lesions in bronchial epithelium of former Chernobyl clean-up workers. Oncogene 21:2398–2405

    Google Scholar 

  7. Connolly DC, Greenspan DL, Wu R, Ren X, Dunn RL, Shah KV, Jones RW, Bosch FX, Munoz N, Cho KR (2000) Loss of fhit expression in invasive cervical carcinomas and intraepithelial lesions associated with invasive disease. Clin Cancer Res 6:3505–3510

    Google Scholar 

  8. Craighead JE, Mossman BT (1982) The pathogenesis of asbestos-associated diseases. N Engl J Med 306:1446–1455

    Google Scholar 

  9. Croce CM, Sozzi G, Huebner K (1999) Role of FHIT in human cancer. J Clin Oncol 17:1618–1624

    Google Scholar 

  10. Deguen B, Goutebroze L, Giovannini M, Boisson C, van der Neut R, Jaurand MC, Thomas G (1998) Heterogeneity of mesothelioma cell lines as defined by altered genomic structure and expression of the NF2 gene. Int J Cancer 77:554–560

    Google Scholar 

  11. De Rienzo A, Testa JR (2000) Recent advances in the molecular analysis of human malignant mesothelioma. Clin Ther 151:433–438

    Google Scholar 

  12. Fong LY, Fidanza V, Zanesi N, Lock LF, Siracusa LD, Mancini R, Siprashvili Z, Ottey M, Martin SE, Druck T, McCue PA, Croce CM, Huebner K (2000) Muir-Torre-like syndrome in Fhit-deficient mice. Proc Natl Acad Sci U S A 97:4742–4747

    Google Scholar 

  13. Geradts J, Fong KM, Zimmerman PV, Minna JD (2000) Loss of Fhit expression in non-small-cell lung cancer: correlation with molecular genetic abnormalities and clinicopathological features. Br J Cancer 82:1191–1197

    Google Scholar 

  14. Guo Z,Johansson SL, Rhim JS, Vishwanatha JK (2000) Fragile histidine triad gene expression in primary prostate cancer and in an in vitro model. Prostate 43:101–110

    Google Scholar 

  15. Hanselaar AG (2002) Additional techniques in serous effusion. Anal Cell Pathol 24:1–4

    Google Scholar 

  16. Hao XP, Willis JE, Pretlow TG, Rao JS, MacLennan GT, Talbot IC, Pretlow TP (2000) Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions. Cancer Res 60:18–21

    Google Scholar 

  17. Hirao T, Nelson HH, Ashok TD, Wain JC, Mark EJ, Christiani DC, Wiencke JK, Kelsey KT (2001) Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer. Cancer Res 61:612–615

    Google Scholar 

  18. Kivipensas P, Bjorkqvist AM, Karhu R, Pelin K, Linnainmaa K, Tammilehto L, Mattson K, Kallioniemi OP, Knuutila S (1996) Gains and losses of DNA sequences in malignant mesothelioma by comparative genomic hybridization. Cancer Genet Cytogenet 89:7–13

    Google Scholar 

  19. Lee WC, Testa JR (1999) Somatic genetic alterations in human malignant mesothelioma. Int J Oncol 14:181–188

    Google Scholar 

  20. Lee JI, Soria JC, Hassan K, Liu D, Tang X, El-Naggar A, Hong WK, Mao L (2001) Loss of Fhit expression is a predictor of poor outcome in tongue cancer. Cancer Res 61:837–841

    Google Scholar 

  21. Lu YY, Jhanwar SC, Cheng JQ, Testa JR (1994) Deletion mapping of the short arm of chromosome 3 in human malignant mesothelioma. Genes Chromosomes Cancer 9:76–80

    Google Scholar 

  22. Nelson HH, Wiencke JK, Gunn L, Wain JC, Christiani DC, Kelsey KT (1998) Chromosome 3p14 alterations in lung cancer: evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos. Cancer Res 58:1804–1807

    Google Scholar 

  23. Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K (1996) The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84:587–597

    CAS  PubMed  Google Scholar 

  24. Pelin-Enlund K, Husgafvel-Pursiainen K, Tammilehto L, Klockars M, Jantunen K, Gerwin BI, Harris CC, Tuomi T, Vanhala E, Mattson K, Linnainmaa K (1990) Asbestos-related malignant mesothelioma: growth, cytology, tumorigenicity and consistent chromosome findings in cell lines from five patients. Carcinogenesis 11:673–681

    Google Scholar 

  25. Prins JB, Williamson KA, Kamp MM, van Hezik EJ, van der Kwast TH, Hagemeijer A, Versnel MA (1998) The gene for the cyclin-dependent-kinase-4 inhibitor, CDKN2A, is preferentially deleted in malignant mesothelioma. Int J Cancer 75:649–653

    Google Scholar 

  26. Pylkkänen L, Wolff H, Stjernvall T, Tuominen P, Sioris T, Karjalainen A, Anttila S, Husgafvel-Pursiainen K (2002) Reduced Fhit protein expression and loss of heterozygosity at FHIT gene in tumours from smoking and asbestos-exposed lung cancer patients. Int J Oncol 20:285–290

    Google Scholar 

  27. Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, Minna JD (1995) Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res 55:1227–1231

    Google Scholar 

  28. Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K (1997) Replacement of Fhit in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci U S A 94:13771–13776

    Google Scholar 

  29. Sorio C, Baron A, Orlandini S, Zamboni G, Pederzoli P, Huebner K, Scarpa A (1999) The FHIT gene is expressed in pancreatic ductular cells and is altered in pancreatic cancers. Cancer Res 59:1308–1314

    Google Scholar 

  30. Sozzi G, Veronese ML, Negrini M, Baffa R, Cotticelli MG, Inoue H, Tornielli S, Pilotti S, De Gregorio L, Pastorino U, Pierotti MA, Ohta M, Huebner K, Croce CM (1996) The FHIT gene 3p14.2 is abnormal in lung cancer. Cell 85:17–26

    Google Scholar 

  31. Sozzi G, Pastorino U, Moiraghi L, Tagliabue E, Pezzella F, Ghirelli C, Tornielli S, Sard L, Huebner K, Pierotti MA, Croce CM, Pilotti S (1998) Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res 58:5032–5037

    CAS  PubMed  Google Scholar 

  32. Taguchi T, Jhanwar SC, Siegfried JM, Keller SM, Testa JR (1993) Recurrent deletions of specific chromosomal sites in 1p, 3p, 6q, and 9p in human malignant mesothelioma. Cancer Res 53:4349–4355

    Google Scholar 

  33. Tomizawa Y, Nakajima T, Kohno T, Saito R, Yamaguchi N, Yokota J (1998) Clinicopathological significance of Fhit protein expression in stage I non-small cell lung carcinoma. Cancer Res 58:5478–5483

    Google Scholar 

  34. Tuomi T, Huuskonen MS, Tammilehto L, Vanhala E, Virtamo M (1991) Occupational exposure to asbestos as evaluated from work histories and analysis of lung tissues from patients with mesothelioma. Br J Int Med 48:48–52

    Google Scholar 

  35. Wistuba II, Behrens C, Virmani AK, Mele G, Milchgrub S, Girard L, Fondon JW 3rd, Garner HR, McKay B, Latif F, Lerman MI, Lam S, Gazdar AF, Minna JD (2000) High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res 60:1949–1960

    Google Scholar 

  36. Yoshino K, Enomoto T, Nakamura T, Sun H, Ozaki K, Nakashima R, Wada H, Saitoh J, Watanabe Y, Noda K, Murata Y (2000) FHIT alterations in cancerous and non-cancerous cervical epithelium. Int J Cancer 85:6–13

    Google Scholar 

  37. Yuan BZ, Keck-Waggoner C, Zimonjic DB, Thorgeirsson SS, Popescu NC (2000) Alterations of the FHIT gene in human hepatocellular carcinoma. Cancer Res 60:1049–1053

    Google Scholar 

  38. Zeiger MA, Gnarra JR, Zbar B, Linehan WM, Pass HI (1994) Loss of heterozygosity on the short arm of chromosome 3 in mesothelioma cell lines and solid tumors. Genes Chromosomes Cancer 11:15–20

    Google Scholar 

  39. Zimmerman RL (2000) FHIT protein is expressed in benign mesothelium and has no clinical value in detecting carcinoma in body cavity effusions. Appl Immunohistochem Molecul Morphol 8:154–157

    Google Scholar 

  40. Zochbauer-Muller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF, Minna JD (2001) 5′ CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. Cancer Res 61:3581–3585

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland

    Lea Pylkkänen & Kirsti Husgafvel-Pursiainen

  2. Department of Occupational Medicine, Finnish Institute of Occupational Health, Helsinki, Finland

    Henrik Wolff, Tuula Stjernvall & Sisko Anttila

  3. Department of Medicine, Division of Respiratory Diseases Helsinki, University Central Hospital, Helsinki, Finland

    Aija Knuuttila

  4. Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 a A, 00250 , Helsinki, Finland

    Kirsti Husgafvel-Pursiainen

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  1. Lea Pylkkänen
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  2. Henrik Wolff
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  6. Kirsti Husgafvel-Pursiainen
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Correspondence to Kirsti Husgafvel-Pursiainen.

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Pylkkänen, L., Wolff, H., Stjernvall, T. et al. Reduced Fhit protein expression in human malignant mesothelioma. Virchows Arch 444, 43–48 (2004). https://doi.org/10.1007/s00428-003-0902-3

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  • DOI: https://doi.org/10.1007/s00428-003-0902-3

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