Loss of Heterozygosity in Lung Diseases

  • Sharon C. Presnell
Part of the Molecular Pathology Library book series (MPLB, volume 1)


Lung cancer remains the leading cause of cancer-related death, accounting for over 1 million deaths per year worldwide.1, 2, 3 Exposure to insult, primarily tobacco smoke, is the indisputable root cause of most lung cancers,4 but it is the consequential epigenetic and genetic changes (promoter methylation, mutations, deletions, and amplifications) that drive tumor formation, progression, and metastasis. Loss of heterozygosity (LOH) is an extremely common genetic feature of lung cancer and is a significant mechanism by which critical genes involved in growth regulation and homeostasis become inactivated, or silenced, during disease evolution. This chapter reviews LOH and its implications in the major classes of lung cancer as well as in nonmalignant lung diseases.


Lung Cancer Chronic Obstructive Pulmonary Disease Tumor Suppressor Gene Candidate Tumor Suppressor Gene FHIT Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Coleman MP, Gatta G, Verdecchia A, et al. EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann Oncol 2003;14(Suppl 5):v128–v149.CrossRefPubMedGoogle Scholar
  2. 2.
    Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer, 1975-2002, featuring population-based trends in cancer treatment. J Natl Cancer Inst 2005;97(19):1407–1427.PubMedGoogle Scholar
  3. 3.
    Knoke JD, Shanks TG, Vaughn JW, Thun MJ, Burns DM. Lung cancer mortality is related to age in addition to duration and intensity of cigarette smoking: an analysis of CPS-I data. Cancer Epidemiol Biomarkers Prev 2004;13(6):949–957.PubMedGoogle Scholar
  4. 4.
    Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55(1):10–30.CrossRefPubMedGoogle Scholar
  5. 5.
    Cecil RL, Goldman L, Ausiello DA. Cecil Textbook of Medicine. 23rd ed. Philadelphia: Saunders Elsevier; 2007.Google Scholar
  6. 6.
    Fong KM, Sekido Y, Minna JD. Molecular pathogenesis of lung cancer. J Thorac Cardiovasc Surg 1999;118(6):1136–1152.CrossRefPubMedGoogle Scholar
  7. 7.
    Sekido Y, Fong KM, Minna JD. Progress in understanding the molecular pathogenesis of human lung cancer. Biochim Biophys Acta 1998;1378(1):F21–F59.PubMedGoogle Scholar
  8. 8.
    Pinkel D, Segraves R, Sudar D, et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 1998;20(2):207–211.CrossRefPubMedGoogle Scholar
  9. 9.
    Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res 2000;60(17):4894–4906.PubMedGoogle Scholar
  10. 10.
    Virmani AK, Fong KM, Kodagoda D, et al. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer 1998;21(4):308–319.CrossRefPubMedGoogle Scholar
  11. 11.
    Lindblad-Toh K, Tanenbaum DM, Daly MJ, et al. Loss-ofheterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nat Biotechnol 2000;18(9):1001–1005.CrossRefPubMedGoogle Scholar
  12. 12.
    Vogelstein B, Fearon ER, Kern SE, et al. Allelotype of colorectal carcinomas. Science 1989;244(4901):207–211.CrossRefPubMedGoogle Scholar
  13. 13.
    Powell CA, Klares S, O’Connor G, Brody JS. Loss of heterozygosity in epithelial cells obtained by bronchial brushing: clinical utility in lung cancer. Clin Cancer Res 1999;5(8):2025–2034.PubMedGoogle Scholar
  14. 14.
    Zabarovsky ER, Lerman MI, Minna JD. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002;21(45):6915–6935.CrossRefPubMedGoogle Scholar
  15. 15.
    Halpern MT, Gillespie BW, Warner KE. Patterns of absolute risk of lung cancer mortality in former smokers. J Natl Cancer Inst 1993;85(6):457–464.CrossRefPubMedGoogle Scholar
  16. 16.
    Wiencke JK, Kelsey KT. Teen smoking, field cancerization, and a “critical period” hypothesis for lung cancer susceptibility. Environ Health Perspect 2002;110(6):555–558.PubMedGoogle Scholar
  17. 17.
    Hirao T, Nelson HH, Ashok TD, et al. Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer. Cancer Res 2001;61(2):612–615.PubMedGoogle Scholar
  18. 18.
    Wiencke JK. DNA adduct burden and tobacco carcinogenesis. Oncogene 2002;21(48):7376–7391.CrossRefPubMedGoogle Scholar
  19. 19.
    Wiencke JK, Nelson HH, Wain JC, Mark EJ, Christiani DC, Kelsey KT. Association of increased PAH-DNA adducts and p53 mutations in lung cancer. Proc Natl Acad Sci USA 1998;39:562.Google Scholar
  20. 20.
    Zienolddiny S, Ryberg D, Arab MO, Skaug V, Haugen A. Loss of heterozygosity is related to p53 mutations and smoking in lung cancer. Br J Cancer 2001;84(2):226–231.CrossRefPubMedGoogle Scholar
  21. 21.
    Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953;6(5):963–968.CrossRefPubMedGoogle Scholar
  22. 22.
    Craighead J, Mossman B. The pathogenesis of asbestosassociated diseases. N Engl J Med 1982;306:1446–1455.PubMedCrossRefGoogle Scholar
  23. 23.
    Pylkkanen L, Wolff H, Stjernvall T, et al. Reduced Fhit protein expression and loss of heterozygosity at FHIT gene in tumours from smoking and asbestos-exposed lung cancer patients. Int J Oncol 2002;20(2):285–290.PubMedGoogle Scholar
  24. 24.
    Both K, Henderson DW, Tumer DR. Asbestos and erionite fibres can induce mutations in human lymphocytes that result in loss of heterozygosity. Int J Cancer 1994;59(4):538–542.CrossRefPubMedGoogle Scholar
  25. 25.
    Tug E, Tug T, Elyas H, et al. Tumor suppressor gene alterations in patients with malignant mesothelioma due to environmental asbestos exposure in Turkey. J Carcinog 2006;5:23–25.CrossRefPubMedGoogle Scholar
  26. 26.
    Wu MS, Shun CT, Wang HP, et al. Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection. Gastroenterology 1997;112(5):1457–1465.CrossRefPubMedGoogle Scholar
  27. 27.
    Song L, Yan W, Deng M, Song S, Zhang J, Zhao T. Aberrations in the fragile histidine triad (FHIT) gene may be involved in lung carcinogenesis in patients with chronic pulmonary tuberculosis. Tumour Biol 2004;25(5–6):270–275.CrossRefPubMedGoogle Scholar
  28. 28.
    Song L, Yan W, Zhao T, et al. Mycobacterium tuberculosis infection and FHIT gene alterations in lung cancer. Cancer Lett 2005;219(2):155–162.CrossRefPubMedGoogle Scholar
  29. 29.
    Brenner C, Bieganowski P, Pace HC, Huebner K. The histidine triad superfamily of nucleotide-binding proteins. J Cell Physiol 1999;181(2):179–187.CrossRefPubMedGoogle Scholar
  30. 30.
    Minna JD, ed. Neoplasms of the Lung. New York: McGraw-Hill; 1994.Google Scholar
  31. 31.
    Shiseki MT, Kohno J, Adachi J, et al. Comparative allelotype of early and advanced stage non-small cell lung carcinomas. Genes Chromosomes Cancer 1996;17:71–77.CrossRefPubMedGoogle Scholar
  32. 32.
    Tseng RC, Chang JW, Hsien FJ, et al. Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int J Cancer 2005;117(2):241–247.CrossRefPubMedGoogle Scholar
  33. 33.
    Yoshino I, Osoegawa A, Yohena T, et al. Loss of heterozygosity (LOH) in non-small cell lung cancer: difference between adenocarcinoma and squamous cell carcinoma. Respir Med 2005;99(3):308–312.CrossRefPubMedGoogle Scholar
  34. 34.
    Pan H, Califano J, Ponte JF, et al. Loss of heterozygosity patterns provide fingerprints for genetic heterogeneity in multistep cancer progression of tobacco smoke-induced non-small cell lung cancer. Cancer Res 2005;65(5):1664–1669.CrossRefPubMedGoogle Scholar
  35. 35.
    Powell CA, Bueno R, Borczuk AC, et al. Patterns of allelic loss differ in lung adenocarcinomas of smokers and nonsmokers. Lung Cancer 2003;39(1):23–29.CrossRefPubMedGoogle Scholar
  36. 36.
    Baksh FK, Dacic S, Finkelstein SD, et al. Widespread molecular alterations present in stage I non-small cell lung carcinoma fail to predict tumor recurrence. Mod Pathol 2003;16(1):28–34.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhou X, Kemp BL, Khuri FR, et al. Prognostic implication of microsatellite alteration profiles in early-stage non-small cell lung cancer. Clin Cancer Res 2000;6(2):559–565.PubMedGoogle Scholar
  38. 38.
    Dacic S, Ionescu DN, Finkelstein S, Yousem SA. Patterns of allelic loss of synchronous adenocarcinomas of the lung. Am J Surg Pathol 2005;29(7):897–902.CrossRefPubMedGoogle Scholar
  39. 39.
    Sasatomi E, Johnson LR, Aldeeb DN, et al. Genetic profile of cumulative mutational damage associated with early pulmonary adenocarcinoma: bronchioloalveolar carcinoma vs. stage I invasive adenocarcinoma. Am J Surg Pathol 2004;28(10):1280–1288.CrossRefPubMedGoogle Scholar
  40. 40.
    Ragnarsson G, Eiriksdottir G, Johannsdottir JT, Jonasson JG, Egilsson V, Ingvarsson S. Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival. Br J Cancer 1999;79(9–10):1468–1474.CrossRefPubMedGoogle Scholar
  41. 41.
    Fang L, Lee SW, Aaronson SA. Comparative analysis of p73 and p53 regulation and effector functions. J Cell Biol 1999;147(4):823–830.CrossRefPubMedGoogle Scholar
  42. 42.
    Gupta S. Molecular steps of tumor necrosis factor receptor-mediated apoptosis. Curr Mol Med 2001;1(3):317–324.CrossRefPubMedGoogle Scholar
  43. 43.
    Wistuba, II, Behrens C, Virmani AK, et al. 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 2000;60(7):1949–1960.PubMedGoogle Scholar
  44. 44.
    Yokota J, Wada M, Shimosato Y, Terada M, Sugimura T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci USA 1987;84(24):9252–9256.CrossRefPubMedGoogle Scholar
  45. 45.
    Toledo G, Sola JJ, Lozano MD, Soria E, Pardo J. Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer. Mod Pathol 2004;17(4):440–448.CrossRefPubMedGoogle Scholar
  46. 46.
    Ohta M, Inoue H, Cotticelli MG, et al. 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 1996;84(4):587–597.CrossRefPubMedGoogle Scholar
  47. 47.
    Fong KM, Biesterveld EJ, Virmani A, et al. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res 1997;57(11):2256–2267.PubMedGoogle Scholar
  48. 48.
    Woenckhaus M, Grepmeier U, Wild PJ, et al. Multitarget FISH and LOH analyses at chromosome 3p in non-small cell lung cancer and adjacent bronchial epithelium. Am J Clin Pathol 2005;123(5):752–761.CrossRefPubMedGoogle Scholar
  49. 49.
    Zanesi N, Fidanza V, Fong LY, et al. The tumor spectrum in FHIT-deficient mice. Proc Natl Acad Sci USA 2001;98(18):10250–10255.CrossRefPubMedGoogle Scholar
  50. 50.
    Ji L, Fang B, Yen N, Fong K, Minna JD, Roth JA. Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. Cancer Res 1999;59(14):3333–3339.PubMedGoogle Scholar
  51. 51.
    Otterson GA, Xiao GH, Geradts J, et al. Protein expression and functional analysis of the FHIT gene in human tumor cells. J Natl Cancer Inst 1998;90(6):426–432.CrossRefPubMedGoogle Scholar
  52. 52.
    Werner NS, Siprashvili Z, Fong LY, et al. Differential susceptibility of renal carcinoma cell lines to tumor suppression by exogenous Fhit expression. Cancer Res 2000;60(11):2780–2785.PubMedGoogle Scholar
  53. 53.
    Marsit CJ, Hasegawa M, Hirao T, et al. Loss of heterozygosity of chromosome 3p21 is associated with mutant TP53 and better patient survival in non-small-cell lung cancer. Cancer Res 2004;64(23):8702–8707.CrossRefPubMedGoogle Scholar
  54. 54.
    Chmara M, Wozniak A, Ochman K, et al. Loss of heterozygosity at chromosomes 3p and 17p in primary non-small cell lung cancer. Anticancer Res 2004;24(6):4259–4263.PubMedGoogle Scholar
  55. 55.
    Ho WL, Chang JW, Tseng RC, et al. Loss of heterozygosity at loci of candidate tumor suppressor genes in microdissected primary non-small cell lung cancer. Cancer Detect Prev 2002;26(5):343–349.CrossRefPubMedGoogle Scholar
  56. 56.
    Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos DA. MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. J Cell Mol Med 2002;6(2):215–222.CrossRefPubMedGoogle Scholar
  57. 57.
    Suzuki M, Hao C, Takahashi T, et al. Aberrant methylation of SPARC in human lung cancers. Br J Cancer 2005;92(5):942–948.CrossRefPubMedGoogle Scholar
  58. 58.
    Sanz-Ortega J, Bryant B, Sanz-Esponera J, et al. LOH at the APC/MCC gene (5Q21) is frequent in early stages of non-small cell lung cancer. Pathol Res Pract 1999;195(10):677–680.PubMedGoogle Scholar
  59. 59.
    Brabender J, Usadel H, Danenberg KD, et al. Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival. Oncogene 2001;20(27):3528–3532.CrossRefPubMedGoogle Scholar
  60. 60.
    Kurimoto F, Gemma A, Hosoya Y, et al. Unchanged frequency of loss of heterozygosity and size of the deleted region at 8p21–23 during metastasis of lung cancer. Int J Mol Med 2001;8(1):89–93.PubMedGoogle Scholar
  61. 61.
    Wistuba, II, Behrens C, Virmani AK, et al. Allelic losses at chromosome 8p21–23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res 1999;59(8):1973–1979.PubMedGoogle Scholar
  62. 62.
    Xu Z, Liang L, Wang H, Li T, Zhao M. HCRP1, a novel gene that is downregulated in hepatocellular carcinoma, encodes a growth-inhibitory protein. Biochem Biophys Res Commun 2003;311(4):1057–1066.CrossRefPubMedGoogle Scholar
  63. 63.
    Marsit CJ, Wiencke JK, Nelson HH, et al. Alterations of 9p in squamous cell carcinoma and adenocarcinoma of the lung: association with smoking, TP53, and survival. Cancer Genet Cytogenet 2005;162(2):115–121.CrossRefPubMedGoogle Scholar
  64. 64.
    Ohtani N, Yamakoshi K, Takahashi A, Hara E. The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest 2004;51(3–4):146–153.CrossRefPubMedGoogle Scholar
  65. 65.
    Sumitomo K, Shimizu E, Shinohara A, Yokota J, Sone S. Activation of RB tumor suppressor protein and growth suppression of small cell lung carcinoma cells by reintroduction of p16INK4A gene. Int J Oncol 1999;14(6):1075–1080.PubMedGoogle Scholar
  66. 66.
    Kratzke RA, Greatens TM, Rubins JB, et al. Rb and p16INK4a expression in resected non-small cell lung tumors. Cancer Res 1996;56(15):3415–2340.PubMedGoogle Scholar
  67. 67.
    Quesnel B, Preudhomme C, Fenaux P. p16ink4a gene and hematological malignancies. Leuk Lymphoma 1996;22(1–2):11–24.PubMedCrossRefGoogle Scholar
  68. 68.
    Awaya H, Takeshima Y, Amatya VJ, et al. Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung. Pathol Int 2004;54(7):486–489.CrossRefPubMedGoogle Scholar
  69. 69.
    Marsit CJ, Zheng S, Aldape K, et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol 2005;36(7):768–776.CrossRefPubMedGoogle Scholar
  70. 70.
    Kim SK, Su LK, Oh Y, et al. Alterations of PTEN/MMAC1, a candidate tumor suppressor gene, and its homologue, PTH2, in small cell lung cancer cell lines. Oncogene 1998;16(1):89–93.CrossRefPubMedGoogle Scholar
  71. 71.
    Hosoya Y, Gemma A, Seike M, et al. Alteration of the PTEN/MMAC1 gene locus in primary lung cancer with distant metastasis. Lung Cancer 1999;25(2):87–93.CrossRefPubMedGoogle Scholar
  72. 72.
    Wikman H, Kettunen E. Regulation of the G1/S phase of the cell cycle and alterations in the RB pathway in human lung cancer. Expert Rev Anticancer Ther 2006;6(4):515–350.CrossRefPubMedGoogle Scholar
  73. 73.
    Arvanitis DA, Papadakis E, Zafiropoulos A, Spandidos DA. Fractional allele loss is a valuable marker for human lung cancer detection in sputum. Lung Cancer 2003;40(1):55–66.CrossRefPubMedGoogle Scholar
  74. 74.
    Gorgoulis VG, Zacharatos P, Kotsinas A, et al. Alterations of the p16-pRb pathway and the chromosome locus 9p21–22 in non-small-cell lung carcinomas: relationship with p53 and MDM2 protein expression. Am J Pathol 1998;153(6):1749–1765.PubMedGoogle Scholar
  75. 75.
    Kee HJ, Shin JH, Chang J, et al. Identification of tumor suppressor loci on the long arm of chromosome 15 in primary small cell lung cancer. Yonsei Med J 2003;44(1):65–74.PubMedGoogle Scholar
  76. 76.
    Stanton SE, Shin SW, Johnson BE, Meyerson M. Recurrent allelic deletions of chromosome arms 15q and 16q in human small cell lung carcinomas. Genes Chromosomes Cancer 2000;27(3):323–331.CrossRefPubMedGoogle Scholar
  77. 77.
    Petersen I, Langreck H, Wolf G, et al. Small-cell lung cancer is characterized by a high incidence of deletions on chromosomes 3p, 4q, 5q, 10q, 13q and 17p. Br J Cancer 1997;75(1):79–86.PubMedGoogle Scholar
  78. 78.
    Hussain SP, Harris CC. p53 biological network: at the crossroads of the cellular-stress response pathway and molecular carcinogenesis. J Nippon Med Sch 2006;73(2):54–64.CrossRefPubMedGoogle Scholar
  79. 79.
    Yang TL, Su YR, Huang CS, et al. High-resolution 19p13. 2–13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity. Genes Chromosomes Cancer 2004;41(3):250–256.CrossRefPubMedGoogle Scholar
  80. 80.
    von Herbay A, Arens N, Friedl W, et al. Bronchioloalveolar carcinoma: a new cancer in Peutz-Jeghers syndrome. Lung Cancer 2005;47(2):283–288.CrossRefGoogle Scholar
  81. 81.
    Sobottka SB, Haase M, Fitze G, Hahn M, Schackert HK, Schackert G. Frequent loss of heterozygosity at the 19p13.3 locus without LKB1/STK11 mutations in human carcinoma metastases to the brain. J Neurooncol 2000;49(3):187–195.CrossRefPubMedGoogle Scholar
  82. 82.
    Samara K, Zervou M, Siafakas NM, Tzortzaki EG. Microsatellite DNA instability in benign lung diseases. Respir Med 2006;100(2):202–211.CrossRefPubMedGoogle Scholar
  83. 83.
    King T. Idiopathic pulmonary fibrosis. In: Schwartz M, King T, eds. Interstitial Lung Disease. Ontario, Canada: Decker BC, Inc.; 1998:597–644.Google Scholar
  84. 84.
    Uematsu K, Yoshimura A, Gemma A, et al. Aberrations in the fragile histidine triad (FHIT) gene in idiopathic pulmonary fibrosis. Cancer Res 2001;61(23):8527–8533.PubMedGoogle Scholar
  85. 85.
    Vassilakis DA, Sourvinos G, Pantelidis P, Spandidos DA, Siafakas NM, Bouros D. Extended genetic alterations in a patient with pulmonary sarcoidosis, a benign disease. Sarcoidosis Vasc Diffuse Lung Dis 2001;18(3):307–310.PubMedGoogle Scholar
  86. 86.
    Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos DA. Genomic instability on hMSH2, hMLH1, CD48 and IRF4 loci in pulmonary sarcoidosis. Int J Biol Markers 2002;17(4):224–230.PubMedGoogle Scholar
  87. 87.
    Xu J, Meyers DA, Ober C, et al. Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am J Hum Genet 2001;68(6):1437–1446.CrossRefPubMedGoogle Scholar
  88. 88.
    Sandford AJ, Pare PD. The genetics of asthma. The important questions. Am J Respir Crit Care Med 2000;161(3 Pt 2):S202–S206.PubMedGoogle Scholar
  89. 89.
    Paraskakis E, Sourvinos G, Passam F, et al. Microsatellite DNA instability and loss of heterozygosity in bronchial asthma. Eur Respir J 2003;22(6):951–955.CrossRefPubMedGoogle Scholar
  90. 90.
    Siafakas NM, Tzortzaki EG, Sourvinos G, et al. Microsatellite DNA instability in COPD. Chest 1999;116(1):47–51.CrossRefPubMedGoogle Scholar
  91. 91.
    Anderson GP, Bozinovski S. Acquired somatic mutations in the molecular pathogenesis of COPD. Trends Pharmacol Sci 2003;24(2):71–76.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Sharon C. Presnell
    • 1
  1. 1.Cell and Tissue TechnologiesBecton DickinsonResearch Triangle ParkUSA

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