Skip to main content
SpringerLink
Log in

Lung Cancer: Molecular Markers

  • Chapter
  • First Online:
Occupational Cancers

Abstract

Lung cancer is the most frequent and one of the most devastating occupational cancers. Therefore, early detection is a major focus area and could be improved by the use of molecular markers. Specific molecular markers are also crucial in the development of molecular diagnosis and molecular targeted treatments. Molecular markers can reflect either the early effects of exposure or the secondary effects of the exposure-related early effects, which are more closely related to the actual disease process. Although early effects may be reversible or have a very low probability of causing the development of a tumor, they can also be closely related to the disease process. To make a molecular marker relevant in disease prevention, it should measure an event in the disease process. Furthermore, it should be able to accommodate individual differences in exposure and susceptibility, be readily detectable, and show a dose–response to the exposure level (Talaska G, Roh J, Zhou Q, Yonsei Med J. 37:1–18, 1996).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Helmig S, Schneider J. Oncogene and tumor-suppressor gene products as serum biomarkers in occupational-derived lung cancer. Expert Rev Mol Diagn. 2007;7:555–68.

    Article  CAS  PubMed  Google Scholar 

  2. Talaska G, Roh J, Zhou Q. Molecular biomarkers of occupational lung cancer. Yonsei Med J. 1996;37:1–18.

    CAS  PubMed  Google Scholar 

  3. Kamp DW. Asbestos-induced lung diseases: an update. Transl Res. 2009;153:143–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Gessner C, Rechner B, Hammerschmidt S, et al. Angiogenic markers in breath condensate identify non-small cell lung cancer. Lung Cancer. 2010;68:177–84.

    Article  CAS  PubMed  Google Scholar 

  5. Corradi M, Gergelova P, Mutti A. Use of exhaled breath condensate to investigate occupational lung diseases. Curr Opin Allergy Clin Immunol. 2010;10(2):93–8.

    Article  CAS  PubMed  Google Scholar 

  6. Mutti A. Molecular diagnosis of lung cancer: an overview of recent developments. Acta Biomedica. 2008;79 Suppl 1:11–23.

    PubMed  Google Scholar 

  7. Carpagnano GE, Foschino-Barbaro MP, Spanevello A, et al. 3p microsatellite signature in exhaled breath condensate and tumor tissue of patients with lung cancer. Am J Resp Crit Care Med. 2008;177:337–41.

    Article  CAS  PubMed  Google Scholar 

  8. Nymark P, Wikman H, Hienonen-Kempas T, Anttila S. Molecular and genetic changes in asbestos-related lung cancer. Cancer Lett. 2008;265:1–15.

    Article  CAS  PubMed  Google Scholar 

  9. Gube M, Taeger D, Weber D, et al. Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos. Arch Toxicol. 2010;85:185–92.

    Article  PubMed  Google Scholar 

  10. Kettunen E, Aavikko M, Nymark P, et al. DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure. Br J Cancer. 2009;100:1336–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Pylkkänen 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;20:285–90.

    PubMed  Google Scholar 

  12. Nelson H, Wiencke J, Gunn L, Wain J, Christiani D, Kelsey K. Chromosome 3p14 alterations in lung cancer: evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos. Cancer Res. 1998;58:1804–7.

    CAS  PubMed  Google Scholar 

  13. 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;64:8702–7.

    Article  CAS  PubMed  Google Scholar 

  14. Nymark P, Wikman H, Ruosaari S, et al. Identification of specific gene copy number changes in asbestos-related lung cancer. Cancer Res. 2006;66:5737–43.

    Article  CAS  PubMed  Google Scholar 

  15. Andujar P, Wang J, Descatha A, et al. p16INK4A inactivation mechanisms in non-small-cell lung cancer patients occupationally exposed to asbestos. Lung Cancer. 2010;67:23–30.

    Article  PubMed  Google Scholar 

  16. Nymark P, Kettunen E, Aavikko M, et al. Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer. Clin Cancer Res. 2009;15:468–75.

    Article  CAS  PubMed  Google Scholar 

  17. Dopp E, Schuler M, Schiffmann D, Eastmond DA. Induction of micronuclei, hyperdiploidy and chromosomal breakage affecting the centric/pericentric regions of chromosomes 1 and 9 in human amniotic fluid cells after treatment with asbestos and ceramic fibers. Mutat Res/Fundam Mol Mech Mutagen. 1997;377:77–87.

    Article  CAS  Google Scholar 

  18. Suzuki M, Piao C, Zhao Y, Hei T. Karyotype analysis of tumorigenic human bronchial epithelial cells transformed by chrysolite asbestos using chemically induced premature chromosome condensation technique. Int J Mol Med. 2001;8:43–7.

    CAS  PubMed  Google Scholar 

  19. Ruosaari S, Nymark P, Aavikko M, et al. Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro. Carcinogenesis. 2008;29:913–7.

    Article  CAS  PubMed  Google Scholar 

  20. Jensen C, Jensen L, Rieder C, Cole R, Ault J. Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis. Carcinogenesis. 1996;17:2013–21.

    Article  CAS  PubMed  Google Scholar 

  21. Mishra A, Liu J, Brody A, Morris G. Inhaled asbestos fibers induce p53 expression in the rat lung. Am J Respir Cell Mol Biol. 1997;16:479–85.

    Article  CAS  PubMed  Google Scholar 

  22. Nuorva K, Mäkitaro R, Huhti E, et al. p53 protein accumulation in lung carcinomas of patients exposed to asbestos and tobacco smoke. Am J Respir Crit Care Med. 1994;150:528–33.

    Article  CAS  PubMed  Google Scholar 

  23. Matsuoka M, Igisu H, Morimoto Y. Phosphorylation of p53 protein in A549 human pulmonary epithelial cells exposed to asbestos fibers. Environ Health Perspect. 2003;111:509–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Pääkkö P, Rämet M, Vähäkangas K, et al. Crocidolite asbestos causes an induction of p53 and apoptosis in cultured A-549 lung carcinoma cells. Apoptosis. 1998;3:203–12.

    Article  PubMed  Google Scholar 

  25. Panduri V, Surapureddi S, Soberanes S, Weitzman SA, Chandel N, Kamp DW. P53 mediates amosite asbestos-induced alveolar epithelial cell mitochondria-regulated apoptosis. Am J Respir Cell Mol Biol. 2006;34:443–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Wang X, Christiani D, Wiencke J, et al. Mutations in the p53 gene in lung cancer are associated with cigarette smoking and asbestos exposure. Cancer Epid Biomark Prev. 1995;4:543–8.

    CAS  Google Scholar 

  27. Liu B, Fu D, Miao Q, Wang H, You B. p53 gene mutations in asbestos associated cancers. Biomed Environ Sci. 1998;11:226–32.

    CAS  PubMed  Google Scholar 

  28. Jaurand M. Mechanisms of fiber-induced genotoxicity. Environ Health Perspect. 1997;105:1073–84.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Brandt-Rauf P, Smith S, Hemminki K, et al. Serum oncoproteins and growth factors in asbestosis and silicosis patients. Int J Cancer. 1992;50:881–5.

    Article  CAS  PubMed  Google Scholar 

  30. Husgafvel-Pursiainen K, Hackman P, Ridanpaa M, et al. K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos. Int J Cancer. 1993;53:250–6.

    Article  CAS  PubMed  Google Scholar 

  31. Nelson HH, Christiani DC, Wiencke JK, Mark EJ, Wain JC, Kelsey KT. k-ras mutation and occupational asbestos exposure in lung adenocarcinoma: asbestos-related cancer without asbestosis. Cancer Res. 1999;59:4570–3.

    CAS  PubMed  Google Scholar 

  32. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers – a different disease. Nat Rev Cancer. 2007;7:778–90.

    Article  CAS  PubMed  Google Scholar 

  33. Lange JH, Hoskins J, Mastrangelo G. Smoking rates in asbestos workers. Occup Med. 2006;56:581.

    Article  Google Scholar 

  34. Lee YJ, Kim J-H, Kim SK, et al. Lung cancer in never smokers: change of a mindset in the molecular era. Lung Cancer. 2011;72:9–15.

    Article  PubMed  Google Scholar 

  35. Pfeifer G, Denissenko M, Olivier M, Tretyakova N, Hecht S, Hainaut P. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene. 2002;21:7435–51.

    Article  CAS  PubMed  Google Scholar 

  36. Vähäkangas KH, Bennett WP, Castrén K, et al. p53 and K-ras mutations in lung cancers from former and never-smoking women. Cancer Res. 2001;61:4350–6.

    PubMed  Google Scholar 

  37. Wikman H, Ruosaari S, Nymark P, et al. Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer. Oncogene. 2007;26:4730–7.

    Article  CAS  PubMed  Google Scholar 

  38. Taniguchi T, Karnan S, Fukui T, et al. Genomic profiling of malignant pleural mesothelioma with array-based comparative genomic hybridization shows frequent non-random chromosomal alteration regions including JUN amplification on 1p32. Cancer Sci. 2007;98:438–46.

    Article  CAS  PubMed  Google Scholar 

  39. Lindholm P, Salmenkivi K, Vauhkonen H, et al. Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH. Cytogenet Genome Res. 2007;119:46.

    Article  CAS  PubMed  Google Scholar 

  40. Christensen BC, Godleski JJ, Marsit CJ, et al. Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma. Carcinogenesis. 2008;29:1555–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Wong L, Zhou J, Anderson D, Kratzke RA. Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung Cancer. 2002;38:131–6.

    Article  PubMed  Google Scholar 

  42. Sekido Y. Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. Cancer Sci. 2010;101:1–6.

    Article  CAS  PubMed  Google Scholar 

  43. Dammann R, Strunnikova M, Schagdarsurengin U, et al. CpG island methylation and expression of tumour-associated genes in lung carcinoma. Eur J Cancer. 2005;41:1223–36.

    Article  CAS  PubMed  Google Scholar 

  44. Kraunz KS, Nelson HH, Lemos M, Godleski JJ, Wiencke JK, Kelsey KT. Homozygous deletion of p16/INK4a and tobacco carcinogen exposure in nonsmall cell lung cancer. Int J Cancer. 2006;118:1364–9.

    Article  CAS  PubMed  Google Scholar 

  45. Mossman BT, Lippmann M, et al. Pulmonary Endpoints (Lung Carcinomas and Asbestosis) Following Inhalation Exposure to Asbestos. Journal of Toxicology and Environmental Health, Part B 2011;14(1–4):76–121.

    Google Scholar 

  46. Ivanov SV, Miller J, Lucito R, et al. Genomic events associated with progression of pleural malignant mesothelioma. Int J Cancer. 2009;124:589–99.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Nymark P, Lindholm P, Korpela M, et al. Specific gene expression profiles in asbestos-exposed epithelial and mesothelial lung cell lines. BMC Genomics. 2007;8:62.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Jean D, Thomas E, Manié, et al. Syntenic relationships between genomic profiles of fiber-induced murine and human malignant mesothelioma. Am J Pathol. 2011;178:881–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Husgafvel-Pursiainen K, Karjalainen A, Kannio A, et al. Lung cancer and past occupational exposure to asbestos. Role of p53 and K-ras mutations. Am J Respir Cell Mol Biol. 1999;20:667–74.

    Article  CAS  PubMed  Google Scholar 

  50. Lin F, Liu Y, Liu Y, Keshava N, Li S. Crocidolite induces cell transformation and p53 gene mutation in BALB/c-3T3 cells. Teratog Carcinog Mutagen. 2000;20:273–81.

    Article  CAS  PubMed  Google Scholar 

  51. DeMarini DM, Landi S, Tian D, et al. Lung tumor KRAS and TP53 mutations in nonsmokers reflect exposure to PAH-Rich coal combustion emissions. Cancer Res. 2001;61:6679–81.

    CAS  PubMed  Google Scholar 

  52. Moyer V, Cistulli C, Vaslet C, Kane A. Oxygen radicals and asbestos carcinogenesis. Environ Health Perspect. 1994;102:131–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Loli P, Topinka J, Georgiadis P, et al. Benzo[a]pyrene-enhanced mutagenesis by asbestos in the lung of lambda-lacI transgenic rats. Mutat Res. 2004;553:79–90.

    Article  CAS  PubMed  Google Scholar 

  54. Schneider J, Presek P, Braun A, et al. p53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer. Br J Cancer. 1999;80:1987–94.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Wild C, Ridanpää M, Anttila S, et al. p53 antibodies in the sera of lung cancer patients: comparison with p53 mutation in the tumour tissue. Int J Cancer. 1995;64:176–81.

    Article  CAS  PubMed  Google Scholar 

  56. Guinee Jr DG, Travis WD, Trivers GE, et al. Gender comparisons in human lung cancer: analysis of p53 mutations, anti-p53 serum antibodies and C-erbB-2 expression. Carcinogenesis. 1995;16:993–1002.

    Article  CAS  PubMed  Google Scholar 

  57. Hei T, Wu L, Piao C. Malignant transformation of immortalized human bronchial epithelial cells by asbestos fibers. Environ Health Perspect. 1997;105:1085–8.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Partanen R, Hemminki K, Koskinen H, Luo J, Carney W, Brandt-Rauf P. The detection of increased amounts of the extracellular domain of the epidermal growth factor receptor in serum during carcinogenesis in asbestosis patients. J Occup Med. 1994;36:1324–8.

    Article  CAS  PubMed  Google Scholar 

  59. Wright CM, Larsen JE, Hayward NK, et al. ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas. Genes Chromosomes Cancer. 2010;49:688–98.

    Article  CAS  PubMed  Google Scholar 

  60. Guled M, Lahti L, Lindholm PM, et al. CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma – a miRNA microarray analysis. Genes Chromosomes Cancer. 2009;48:615–23.

    Article  CAS  PubMed  Google Scholar 

  61. Gee GV, Koestler DC, Christensen BC, et al. Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma. Int J Cancer. 2010;127:2859–69.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Yasuda M, Hanagiri T, Shigematsu Y, et al. Identification of a tumour associated antigen in lung cancer patients with asbestos exposure. Anticancer Res. 2010;30:2631–9.

    CAS  PubMed  Google Scholar 

  63. Nair VS, Maeda LS, Ioannidis JPA. Clinical outcome prediction by microRNAs in human cancer: a systematic review. JNCI. 2012;104:528–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Nymark P, Guled M, Borze I, et al. Integrative analysis of microRNA, mRNA and aCGH data reveals asbestos- and histology-related changes in lung cancer. Genes Chromosomes Cancer. 2011;50:585–97.

    Article  CAS  PubMed  Google Scholar 

  65. Nymark P, Aavikko M, Mäkilä J, Ruosaari S, Hienonen-Kempas T, Wikman H, Salmenkivi K, Pirinen R, Karjalainen A, Vanhala E, Kuosma E, Anttila S, Kettunen E. Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients. Mol Oncol. 2013;1:29–40.

    Article  Google Scholar 

  66. Martinez VD, Buys TPH, Adonis M, et al. Arsenic-related DNA copy-number alterations in lung squamous cell carcinomas. Br J Cancer. 2010;103:1277–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Kondo K, Takahashi Y, Hirose Y, et al. The reduced expression and aberrant methylation of p16INK4a in chromate workers with lung cancer. Lung Cancer. 2006;53:295–302.

    Article  PubMed  Google Scholar 

  68. Ali AHK, Kondo K, Namura T, et al. Aberrant DNA methylation of some tumor suppressor genes in lung cancers from workers with chromate exposure. Mol Carcinog. 2011;50:89–99.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The writing of this chapter was financially supported by the Jalmari and Rauha Ahokas Foundation, Helsinki (PN), and Helsinki and Uusimaa Health Care District Research Funds (SA).

Author information

Authors and Affiliations

  1. Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands

    Penny E. H. Nymark PhD

  2. Jorvi Hospital Laboratory of Pathology, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Laboratory Services, HUSLAB, Helsinki, Finland

    Sisko Anttila MD, PhD

  3. Health and Work Ability, Finnish Institute of Occupational Health, Helsinki, Finland

    Sisko Anttila MD, PhD

Authors
  1. Penny E. H. Nymark PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sisko Anttila MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sisko Anttila MD, PhD .

Editor information

Editors and Affiliations

  1. Helsinki University Central Hospital and Finnish Institute of Occupational Health, Helsinki, Finland

    Sisko Anttila

  2. Icahn School of Medicine at Mount Sinai, New York, New York, USA

    Paolo Boffetta

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag London

About this chapter

Cite this chapter

Nymark, P.E.H., Anttila, S. (2014). Lung Cancer: Molecular Markers. In: Anttila, S., Boffetta, P. (eds) Occupational Cancers. Springer, London. https://doi.org/10.1007/978-1-4471-2825-0_12

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-2825-0_12

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-2824-3

  • Online ISBN: 978-1-4471-2825-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation