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. 2007 May 1;6(2):215–222. doi: 10.1111/j.1582-4934.2002.tb00188.x

MYCL1, FHIT, SPARC, p16INK4 and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis

K Demopoulos 1, D A Arvanitis 1, D A Vassilakis 1,2, N M Siafakas 2, D A Spandidos 1,✉
PMCID: PMC6740283  PMID: 12169206

Abstract

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial pneumonia limited to the lung and characterized by a fibroproliferative response with only minor signs of inflammation, which almost always causes rapid fibrotic destruction of the lung. In this study, we investigated genomic instability in IPF, using microsatellite DNA analysis, aiming to detect any specific genetic alterations for this disease. We used 40 highly polymorphic microsatellite DNA markers, in multiplex PCR assays, to examine 52 sputum specimens from IPF patients versus correspondent venous blood. Loss of heterozygosity (LOH) was found in 20 (38.5%) patients in at least one locus. These alterations were found on markers previously associated with lung cancer located on 1p34.3, 3p21.32‐p21.1, 5q32‐q33.1, 9p21 and 17p13.1 where MYCL1, FHIT, SPARC, p16Ink4 and TP53 genes have been mapped respectively. These data provide new insights into IPF pathogenesis and a new perspective for its correlation with lung cancer.

Keywords: idiopathic pulmonary fibrosis, microsatellite DNA, loss of heterozygosity

References

  • 1. Gross T.J., Hunninghake G.W., Idiopathic pulmonary fibrosis, N. Engl. J. Med., 345: 517–525, 2001. [DOI] [PubMed] [Google Scholar]
  • 2. Ziesche R., Hofbauer E., Wittmann K., Petkov V., Block L.H., A preliminary study of long‐term treatment with interferon gamma‐1b and low‐dose prednisolone in patients with idiopathic pulmonary fibrosis, N. Engl. J. Med., 341: 1264–1269, 1999. [DOI] [PubMed] [Google Scholar]
  • 3. Iwai K., Mori T., Yamada N., Yamaguchi M., Hosoda Y., Idiopathic pulmonary fibrosis. Epidemiologic approaches to occupational exposure, Am. J. Respir. Crit. Care Med., 150: 670–675, 1994. [DOI] [PubMed] [Google Scholar]
  • 4. Scott J., Johnston I., Britton J., What causes cryptogenic fibrosing alveolitis? A case‐control study of environmental exposure to dust, Br. Med. J., 301: 1015–1017, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Jakab G.J., Sequential virus infections, bacterial superinfections, and fibrogenesis, Am. Rev. Respi.r Dis., 142: 374–379, 1990. [DOI] [PubMed] [Google Scholar]
  • 6. Lok S.S., Egan J.J., Viruses and idiopathic pulmonary fibrosis, Monaldi Arch. Chest Dis., 55: 146–150, 2000. [PubMed] [Google Scholar]
  • 7. American Thoracic Society . Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS), Am. J. Respir. Crit. Care Med., 161: 646–664, 2000. [DOI] [PubMed] [Google Scholar]
  • 8. Mageto Y.N., Raghu G., Genetic predisposition of idiopathic pulmonary fibrosis, Curr. Opin. Pulm. Med., 3: 336–340, 1997. [DOI] [PubMed] [Google Scholar]
  • 9. Marshall R.P., McAnulty R.J., Laurent G.J., The pathogenesis of pulmonary fibrosis: is there a fibrosis gene?, Int. J. Biochem. Cell Biol., 29: 107–120, 1997. [DOI] [PubMed] [Google Scholar]
  • 10. Marshall R.P., Puddicombe A., Cookson W.O., Laurent G.J., Adult familial cryptogenic fibrosing alveolitis in the United Kingdom, Thorax, 55: 143–146, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Haddad R., Massaro D., Idiopathic diffuse interstitial pulmonary fibrosis (fibrosing alveolitis), atypical epithelial proliferation and lung cancer, Am. J. Med., 45: 211–219, 1968. [DOI] [PubMed] [Google Scholar]
  • 12. Jones A.W., Alveolar cell carcinoma occurring in idiopathic interstitial pulmonary fibrosis, Br. J. Dis. Chest, 64: 78–84, 1970. [DOI] [PubMed] [Google Scholar]
  • 13. Panos R.J., Mortenson R.L., Niccoli S.A., King T.E., Jr. , Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment, Am. J. Med., 88: 396–404, 1990. [DOI] [PubMed] [Google Scholar]
  • 14. Samet J.M., Does idiopathic pulmonary fibrosis increase lung cancer risk?, Am. J. Respir. Crit. Care Med., 161: 1–2, 2000. [DOI] [PubMed] [Google Scholar]
  • 15. Kuwano K., Kunitake R., Kawasaki M., Nomoto Y., Hagimoto N., Nakanishi Y., Hara N., P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care Med., 154: 477–483, 1996. [DOI] [PubMed] [Google Scholar]
  • 16. van den Blink, B. , Jansen H.M., Peppelenbosch M.P., Idiopathic pulmonary fibrosis: molecular mechanisms and possible therapeutic strategies, Arch. Immunol. Ther. Exp. (Warsz.), 48: 539–545, 2000. [PubMed] [Google Scholar]
  • 17. Kawasaki H., Ogura T., Yokose T., Nagai K., Nishiwaki Y., Esumi H., p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis, Hum. Pathol., 32: 1043–1049, 2001. [DOI] [PubMed] [Google Scholar]
  • 18. Maeyama T., Kuwano K., Kawasaki M., Kunitake R., Hagimoto N., Matsuba T., Yoshimi M., Inoshima I., Yoshida K., Hara N., Upregulation of Fas‐signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis, Eur. Respir. J., 17: 180–189, 2001. [DOI] [PubMed] [Google Scholar]
  • 19. Vassilakis D.A., Sourvinos G., Spandidos D.A., Siafakas N.M., Bouros D., Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis, Am. J. Respir. Crit. Care. Med., 162: 1115–1119, 2000. [DOI] [PubMed] [Google Scholar]
  • 20. Mori M., Kida H., Morishita H., Goya S., Matsuoka H., Arai T., Osaki T., Tachibana I., Yamamoto S., Sakatani M., Ito M., Ogura T., Hayashi S., Microsatellite instability in transforming growth factor‐beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis, Am. J. Respir. Cell Mol. Biol., 24: 398–404, 2001. [DOI] [PubMed] [Google Scholar]
  • 21. Uematsu K., Yoshimura A., Gemma A., Mochimaru H., Hosoya Y., Kunugi S., Matsuda K., Seike M., Kurimoto F., Takenaka K., Koizumi K., Fukuda Y., Tanaka S., Chin K., Jablons D.M., Kudoh S., Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis, Cancer Res., 61: 8527–8533, 2001. [PubMed] [Google Scholar]
  • 22. Froudarakis M.E., Sourvinos G., Fournel P., Bouros D., Vergnon J.M., Spandidos D.A., Siafakas N.M., Microsatellite instability and loss of heterozygosity at chromosomes 9 and 17 in nonsmall cell lung cancer, Chest, 113: 1091–1094, 1998. [DOI] [PubMed] [Google Scholar]
  • 23. Bhowmik A., Seemungal T.A., Sapsford R.J., Devalia J.L., Wedzicha J.A., Comparison of spontaneous and induced sputum for investigation of airway inflammation in chronic obstructive pulmonary disease, Thorax, 53: 953–956, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Peltomaki P., Lothe R.A., Aaltonen L.A., Pylkkanen L., Nystrom‐Lahti M., Seruca R., David L., Holm R., Ryberg D., Haugen A., et al., Microsatellite instability is associated with tumors that characterize the hereditary non‐polyposis colorectal carcinoma syndrome, Cancer Res., 53: 5853–5855, 1993. [PubMed] [Google Scholar]
  • 25. DePinho R.A., Hatton K.S., Tesfaye A., Yancopoulos G.D., Alt F.W., The human myc gene family: structure and activity of L‐myc and an Lmyc pseudogene, Genes Dev., 1: 1311–1326, 1987. [DOI] [PubMed] [Google Scholar]
  • 26. Makela T.P., Saksela K., Alitalo K., Amplification and rearrangement of L‐myc in human small‐cell lung cancer, Mutat. Res., 276: 307–315, 1992. [DOI] [PubMed] [Google Scholar]
  • 27. Gasparian A.V., Laktionov K.K., Belialova M.S., Pirogova N.A., Tatosyan A.G., Zborovskaya I.B., Allelic imbalance and instability of microsatellite loci on chromosome 1p in human non‐small‐cell lung cancer, Br. J. Cancer, 77: 1604–1611, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Sozzi G., Veronese M.L., Negrini M., Baffa R., Cotticelli M.G., Inoue H., Tornielli S., Pilotti S., De Gregorio L., Pastorino U., Pierotti M.A., Ohta M., Huebner K., Croce C.M., The FHIT gene 3p14.2 is abnormal in lung cancer, Cell, 85: 17–26, 1996. [DOI] [PubMed] [Google Scholar]
  • 29. Burke L., Khan M.A., Freedman A.N., Gemma A., Rusin M., Guinee D.G., Bennett W.P., Caporaso N.E., Fleming M.V., Travis W.D., Colby T.V., Trastek V., Pairolero P.C., Tazelaar H.D., Midthun D.E., Liotta L.A., Harris C.C., Allelic deletion analysis of the FHIT gene predicts poor survival in non‐small cell lung cancer, Cancer Res., 58: 2533–2536, 1998. [PubMed] [Google Scholar]
  • 30. Bradshaw A.D., Sage E.H., SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury, J. Clin. Invest., 107: 1049–1054, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Selman M., Pardo A., Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross‐talk disorder, Respir. Res., 3: 3, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]

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