Skip to main content

Clinical Implications of Epigenetic Alterations in Human Thoracic Malignancies: Epigenetic Alterations in Lung Cancer

  • Protocol
  • First Online:
Cancer Epigenetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 863))

Abstract

Besides known genetic aberrations, epigenetic alterations have emerged as common hallmarks of many cancer types, including lung cancer. Epigenetics is a process involved in gene regulation, mediated via DNA methylation, histone modification, chromatin remodeling, and functional noncoding RNAs, which influences the accessibility of the underlying DNA to transcriptional regulatory factors that activate or repress expression. Studies have shown that epigenetic dysregulation is associated with multiple steps during carcinogenesis. Since epigenetic therapy is now in clinical use in hematopoietic diseases and undergoing trials for lung cancer, a better understanding of epigenetic abnormalities is desired. Recent technologies for high-throughput genome-wide analyses for epigenetic modifications are promising and potent tools for understanding the global dysregulation of cancer epigenetics. In this chapter, studies of epigenetic abnormality and its clinical implication in lung cancers are discussed.

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

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jemal, A., Siegel, R., Xu, J., and Ward, E. (2010) Cancer statistics, 2010, CA Cancer J Clin 60, 277–300.

    Article  PubMed  Google Scholar 

  2. Ferlay, J., Parkin, D. M., and Steliarova-Foucher, E. (2010) Estimates of cancer incidence and mortality in Europe in 2008, Eur J Cancer 46, 765–781.

    Article  PubMed  CAS  Google Scholar 

  3. Mok, T. S., Wu, Y. L., Thongprasert, S., Yang, C. H., Chu, D. T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., Nishiwaki, Y., Ohe, Y., Yang, J. J., Chewaskulyong, B., Jiang, H., Duffield, E. L., Watkins, C. L., Armour, A. A., and Fukuoka, M. (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N Engl J Med 361, 947–957.

    Article  PubMed  CAS  Google Scholar 

  4. Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., Okamoto, I., Tsurutani, J., Seto, T., Satouchi, M., Tada, H., Hirashima, T., Asami, K., Katakami, N., Takada, M., Yoshioka, H., Shibata, K., Kudoh, S., Shimizu, E., Saito, H., Toyooka, S., Nakagawa, K., and Fukuoka, M. (2010) Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial, Lancet Oncol 11, 121–128.

    Article  PubMed  CAS  Google Scholar 

  5. Choi, Y. L., Soda, M., Yamashita, Y., Ueno, T., Takashima, J., Nakajima, T., Yatabe, Y., Takeuchi, K., Hamada, T., Haruta, H., Ishikawa, Y., Kimura, H., Mitsudomi, T., Tanio, Y., and Mano, H. (2010) EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors, N Engl J Med 363, 1734–1739.

    Article  PubMed  CAS  Google Scholar 

  6. Belinsky, S. A. (2004) Gene-promoter hypermethylation as a biomarker in lung cancer, Nat Rev Cancer 4, 707–717.

    Article  PubMed  CAS  Google Scholar 

  7. Jones, P. A., and Laird, P. W. (1999) Cancer epigenetics comes of age, Nat Genet 21, 163–167.

    Article  PubMed  CAS  Google Scholar 

  8. Jones, P. A., and Baylin, S. B. (2007) The epigenomics of cancer, Cell 128, 683–692.

    Article  PubMed  CAS  Google Scholar 

  9. Brock, M. V., Hooker, C. M., Ota-Machida, E., Han, Y., Guo, M., Ames, S., Glockner, S., Piantadosi, S., Gabrielson, E., Pridham, G., Pelosky, K., Belinsky, S. A., Yang, S. C., Baylin, S. B., and Herman, J. G. (2008) DNA methylation markers and early recurrence in stage I lung cancer, N Engl J Med 358, 1118–1128.

    Article  PubMed  CAS  Google Scholar 

  10. Shen, L., Catalano, P. J., Benson, A. B., 3rd, O’Dwyer, P., Hamilton, S. R., and Issa, J. P. (2007) Association between DNA methylation and shortened survival in patients with advanced colorectal cancer treated with 5-fluorouracil based chemotherapy, Clin Cancer Res 13, 6093–6098.

    Article  PubMed  CAS  Google Scholar 

  11. Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., Verhaak, R. G., Hoadley, K. A., Hayes, D. N., Perou, C. M., Schmidt, H. K., Ding, L., Wilson, R. K., Van Den Berg, D., Shen, H., Bengtsson, H., Neuvial, P., Cope, L. M., Buckley, J., Herman, J. G., Baylin, S. B., Laird, P. W., and Aldape, K. (2010) Identification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma, Cancer Cell 17, 510–522.

    Article  PubMed  CAS  Google Scholar 

  12. Palmisano, W. A., Divine, K. K., Saccomanno, G., Gilliland, F. D., Baylin, S. B., Herman, J. G., and Belinsky, S. A. (2000) Predicting lung cancer by detecting aberrant promoter methylation in sputum, Cancer Res 60, 5954–5958.

    PubMed  CAS  Google Scholar 

  13. Laird, P. W. (2010) Principles and challenges of genome-wide DNA methylation analysis, Nat Rev Genet 11, 191–203.

    Article  PubMed  CAS  Google Scholar 

  14. Brauch, H., Johnson, B., Hovis, J., Yano, T., Gazdar, A., Pettengill, O. S., Graziano, S., Sorenson, G. D., Poiesz, B. J., Minna, J. (1987) Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung, N Engl J Med 317, 1109–1113.

    Article  PubMed  CAS  Google Scholar 

  15. Hibi, K., Takahashi, T., Yamakawa, K., Ueda, R., Sekido, Y., Ariyoshi, Y., Suyama, M., Takagi, H., and Nakamura, Y. (1992) Three distinct regions involved in 3p deletion in human lung cancer, Oncogene 7, 445–449.

    PubMed  CAS  Google Scholar 

  16. Zabarovsky, E. R., Lerman, M. I., and Minna, J. D. (2002) Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers, Oncogene 21, 6915–6935.

    Article  PubMed  CAS  Google Scholar 

  17. Takahashi, T., Nau, M. M., Chiba, I., Birrer, M. J., Rosenberg, R. K., Vinocour, M., Levitt, M., Pass, H., Gazdar, A. F., and Minna, J. D. (1989) p53: a frequent target for genetic abnormalities in lung cancer, Science 246, 491–494.

    Article  PubMed  CAS  Google Scholar 

  18. Forbes, S. A., Tang, G., Bindal, N., Bamford, S., Dawson, E., Cole, C., Kok, C. Y., Jia, M., Ewing, R., Menzies, A., Teague, J. W., Stratton, M. R., and Futreal, P. A. (2010) COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer, Nucleic Acids Res 38, D652–657.

    Article  PubMed  CAS  Google Scholar 

  19. Wistuba, II, Gazdar, A. F., and Minna, J. D. (2001) Molecular genetics of small cell lung carcinoma, Semin Oncol 28, 3–13.

    Article  PubMed  CAS  Google Scholar 

  20. Mounawar, M., Mukeria, A., Le Calvez, F., Hung, R. J., Renard, H., Cortot, A., Bollart, C., Zaridze, D., Brennan, P., Boffetta, P., Brambilla, E., and Hainaut, P. (2007) Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history, Cancer Res 67, 5667–5672.

    Article  PubMed  CAS  Google Scholar 

  21. Kosaka, T., Yatabe, Y., Endoh, H., Kuwano, H., Takahashi, T., and Mitsudomi, T. (2004) Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications, Cancer Res 64, 8919–8923.

    Article  PubMed  CAS  Google Scholar 

  22. Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, II, Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., Fujisawa, T., Feng, Z., Roth, J. A., Herz, J., Minna, J. D., and Gazdar, A. F. (2005) Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers, J Natl Cancer Inst 97, 339–346.

    Article  PubMed  CAS  Google Scholar 

  23. Sharma, S. V., Bell, D. W., Settleman, J., and Haber, D. A. (2007) Epidermal growth factor receptor mutations in lung cancer, Nat Rev Cancer 7, 169–181.

    Article  PubMed  CAS  Google Scholar 

  24. Le Calvez, F., Mukeria, A., Hunt, J. D., Kelm, O., Hung, R. J., Taniere, P., Brennan, P., Boffetta, P., Zaridze, D. G., and Hainaut, P. (2005) TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers, Cancer Res 65, 5076–5083.

    Article  PubMed  Google Scholar 

  25. Mascaux, C., Iannino, N., Martin, B., Paesmans, M., Berghmans, T., Dusart, M., Haller, A., Lothaire, P., Meert, A. P., Noel, S., Lafitte, J. J., and Sculier, J. P. (2005) The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis, Br J Cancer 92, 131–139.

    Article  PubMed  CAS  Google Scholar 

  26. Linardou, H., Dahabreh, I. J., Kanaloupiti, D., Siannis, F., Bafaloukos, D., Kosmidis, P., Papadimitriou, C. A., and Murray, S. (2008) Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer, Lancet Oncol 9, 962–972.

    Article  PubMed  CAS  Google Scholar 

  27. Wong, D. W., Leung, E. L., So, K. K., Tam, I. Y., Sihoe, A. D., Cheng, L. C., Ho, K. K., Au, J. S., Chung, L. P., and Pik Wong, M. (2009) The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS, Cancer 115, 1723–1733.

    Article  PubMed  CAS  Google Scholar 

  28. Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., Fulton, L., Fulton, R. S., Zhang, Q., Wendl, M. C., Lawrence, M. S., Larson, D. E., Chen, K., Dooling, D. J., Sabo, A., Hawes, A. C., Shen, H., Jhangiani, S. N., Lewis, L. R., Hall, O., Zhu, Y., Mathew, T., Ren, Y., Yao, J., Scherer, S. E., Clerc, K., Metcalf, G. A., Ng, B., Milosavljevic, A., Gonzalez-Garay, M. L., Osborne, J. R., Meyer, R., Shi, X., Tang, Y., Koboldt, D. C., Lin, L., Abbott, R., Miner, T. L., Pohl, C., Fewell, G., Haipek, C., Schmidt, H., Dunford-Shore, B. H., Kraja, A., Crosby, S. D., Sawyer, C. S., Vickery, T., Sander, S., Robinson, J., Winckler, W., Baldwin, J., Chirieac, L. R., Dutt, A., Fennell, T., Hanna, M., Johnson, B. E., Onofrio, R. C., Thomas, R. K., Tonon, G., Weir, B. A., Zhao, X., Ziaugra, L., Zody, M. C., Giordano, T., Orringer, M. B., Roth, J. A., Spitz, M. R., Wistuba, II, Ozenberger, B., Good, P. J., Chang, A. C., Beer, D. G., Watson, M. A., Ladanyi, M., Broderick, S., Yoshizawa, A., Travis, W. D., Pao, W., Province, M. A., Weinstock, G. M., Varmus, H. E., Gabriel, S. B., Lander, E. S., Gibbs, R. A., Meyerson, M., and Wilson, R. K. (2008) Somatic mutations affect key pathways in lung adenocarcinoma, Nature 455, 1069–1075.

    Article  PubMed  CAS  Google Scholar 

  29. Jones, P. A., and Baylin, S. B. (2002) The fundamental role of epigenetic events in cancer, Nat Rev Genet 3, 415–428.

    Article  PubMed  CAS  Google Scholar 

  30. Belinsky, S. A., Palmisano, W. A., Gilliland, F. D., Crooks, L. A., Divine, K. K., Winters, S. A., Grimes, M. J., Harms, H. J., Tellez, C. S., Smith, T. M., Moots, P. P., Lechner, J. F., Stidley, C. A., and Crowell, R. E. (2002) Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers, Cancer Res 62, 2370–2377.

    PubMed  CAS  Google Scholar 

  31. Toyota, M., Ahuja, N., Ohe-Toyota, M., Herman, J. G., Baylin, S. B., and Issa, J. P. (1999) CpG island methylator phenotype in colorectal cancer, Proc Natl Acad Sci U S A 96, 8681–8686.

    Article  PubMed  CAS  Google Scholar 

  32. Issa, J. P. (2004) CpG island methylator phenotype in cancer, Nat Rev Cancer 4, 988–993.

    Article  PubMed  CAS  Google Scholar 

  33. Grady, W. M. (2007) CIMP and colon cancer gets more complicated, Gut 56, 1498–1500.

    Article  PubMed  CAS  Google Scholar 

  34. Suzuki, M., Shigematsu, H., Iizasa, T., Hiroshima, K., Nakatani, Y., Minna, J. D., Gazdar, A. F., and Fujisawa, T. (2006) Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer, Cancer 106, 2200–2207.

    Article  PubMed  CAS  Google Scholar 

  35. Liu, Z., Zhao, J., Chen, X. F., Li, W., Liu, R., Lei, Z., Liu, X., Peng, X., Xu, K., Chen, J., Liu, H., Zhou, Q. H., and Zhang, H. T. (2008) CpG island methylator phenotype involving tumor suppressor genes located on chromosome 3p in non-small cell lung cancer, Lung cancer 62, 15–22.

    Article  PubMed  CAS  Google Scholar 

  36. Goto, Y., Shinjo, K., Kondo, Y., Shen, L., Toyota, M., Suzuki, H., Gao, W., An, B., Fujii, M., Murakami, H., Osada, H., Taniguchi, T., Usami, N., Kondo, M., Hasegawa, Y., Shimokata, K., Matsuo, K., Hida, T., Fujimoto, N., Kishimoto, T., Issa, J. P., and Sekido, Y. (2009) Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma, Cancer Res 69, 9073–9082.

    Article  PubMed  CAS  Google Scholar 

  37. Toyooka, S., Tokumo, M., Shigematsu, H., Matsuo, K., Asano, H., Tomii, K., Ichihara, S., Suzuki, M., Aoe, M., Date, H., Gazdar, A. F., and Shimizu, N. (2006) Mutational and epigenetic evidence for independent pathways for lung adenocarcinomas arising in smokers and never smokers, Cancer Res 66, 1371–1375.

    Article  PubMed  CAS  Google Scholar 

  38. Dai, Z., Lakshmanan, R. R., Zhu, W. G., Smiraglia, D. J., Rush, L. J., Fruhwald, M. C., Brena, R. M., Li, B., Wright, F. A., Ross, P., Otterson, G. A., and Plass, C. (2001) Global methylation profiling of lung cancer identifies novel methylated genes, Neoplasia 3, 314–323.

    Article  PubMed  CAS  Google Scholar 

  39. Brena, R. M., Morrison, C., Liyanarachchi, S., Jarjoura, D., Davuluri, R. V., Otterson, G. A., Reisman, D., Glaros, S., Rush, L. J., and Plass, C. (2007) Aberrant DNA methylation of OLIG1, a novel prognostic factor in non-small cell lung cancer, PLoS medicine 4, e108.

    Article  PubMed  Google Scholar 

  40. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G., and Baylin, S. B. (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer, Nat Genet 21, 103–107.

    Article  PubMed  CAS  Google Scholar 

  41. Shames, D. S., Girard, L., Gao, B., Sato, M., Lewis, C. M., Shivapurkar, N., Jiang, A., Perou, C. M., Kim, Y. H., Pollack, J. R., Fong, K. M., Lam, C. L., Wong, M., Shyr, Y., Nanda, R., Olopade, O. I., Gerald, W., Euhus, D. M., Shay, J. W., Gazdar, A. F., and Minna, J. D. (2006) A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies, PLoS medicine 3, e486.

    Article  PubMed  Google Scholar 

  42. Zhong, S., Fields, C. R., Su, N., Pan, Y. X., and Robertson, K. D. (2007) Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer, Oncogene 26, 2621–2634.

    Article  PubMed  CAS  Google Scholar 

  43. Bibikova, M., Lin, Z., Zhou, L., Chudin, E., Garcia, E. W., Wu, B., Doucet, D., Thomas, N. J., Wang, Y., Vollmer, E., Goldmann, T., Seifart, C., Jiang, W., Barker, D. L., Chee, M. S., Floros, J., and Fan, J. B. (2006) High-throughput DNA methylation profiling using universal bead arrays, Genome Res 16, 383–393.

    Article  PubMed  CAS  Google Scholar 

  44. Christensen, B. C., Marsit, C. J., Houseman, E. A., Godleski, J. J., Longacker, J. L., Zheng, S., Yeh, R. F., Wrensch, M. R., Wiemels, J. L., Karagas, M. R., Bueno, R., Sugarbaker, D. J., Nelson, H. H., Wiencke, J. K., and Kelsey, K. T. (2009) Differentiation of lung adenocarcinoma, pleural mesothelioma, and nonmalignant pulmonary tissues using DNA methylation profiles, Cancer Res 69, 6315–6321.

    Article  PubMed  CAS  Google Scholar 

  45. Rauch, T., Wang, Z., Zhang, X., Zhong, X., Wu, X., Lau, S. K., Kernstine, K. H., Riggs, A. D., and Pfeifer, G. P. (2007) Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay, Proc Natl Acad Sci U S A 104, 5527–5532.

    Article  PubMed  CAS  Google Scholar 

  46. Rauch, T. A., Zhong, X., Wu, X., Wang, M., Kernstine, K. H., Wang, Z., Riggs, A. D., and Pfeifer, G. P. (2008) High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer, Proc Natl Acad Sci U S A 105, 252–257.

    Article  PubMed  CAS  Google Scholar 

  47. Fukasawa, M., Kimura, M., Morita, S., Matsubara, K., Yamanaka, S., Endo, C., Sakurada, A., Sato, M., Kondo, T., Horii, A., Sasaki, H., and Hatada, I. (2006) Microarray analysis of promoter methylation in lung cancers, J Hum Genet 51, 368–374.

    Article  PubMed  CAS  Google Scholar 

  48. Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., Gnirke, A., Jaenisch, R., and Lander, E. S. (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells, Nature 454, 766–770.

    PubMed  CAS  Google Scholar 

  49. Lister, R., Pelizzola, M., Dowen, R. H., Hawkins, R. D., Hon, G., Tonti-Filippini, J., Nery, J. R., Lee, L., Ye, Z., Ngo, Q. M., Edsall, L., Antosiewicz-Bourget, J., Stewart, R., Ruotti, V., Millar, A. H., Thomson, J. A., Ren, B., and Ecker, J. R. (2009) Human DNA methylomes at base resolution show widespread epigenomic differences, Nature 462, 315–322.

    Article  PubMed  CAS  Google Scholar 

  50. Licchesi, J. D., Westra, W. H., Hooker, C. M., and Herman, J. G. (2008) Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung, Clin Cancer Res 14, 2570–2578.

    Article  PubMed  CAS  Google Scholar 

  51. Belinsky, S. A., Liechty, K. C., Gentry, F. D., Wolf, H. J., Rogers, J., Vu, K., Haney, J., Kennedy, T. C., Hirsch, F. R., Miller, Y., Franklin, W. A., Herman, J. G., Baylin, S. B., Bunn, P. A., and Byers, T. (2006) Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort, Cancer Res 66, 3338–3344.

    Article  PubMed  CAS  Google Scholar 

  52. Schmiemann, V., Bocking, A., Kazimirek, M., Onofre, A. S., Gabbert, H. E., Kappes, R., Gerharz, C. D., and Grote, H. J. (2005) Methylation assay for the diagnosis of lung cancer on bronchial aspirates: a cohort study, Clin Cancer Res 11, 7728–7734.

    Article  PubMed  CAS  Google Scholar 

  53. Belinsky, S. A., Klinge, D. M., Dekker, J. D., Smith, M. W., Bocklage, T. J., Gilliland, F. D., Crowell, R. E., Karp, D. D., Stidley, C. A., and Picchi, M. A. (2005) Gene promoter methylation in plasma and sputum increases with lung cancer risk, Clin Cancer Res 11, 6505–6511.

    Article  PubMed  CAS  Google Scholar 

  54. Fujiwara, K., Fujimoto, N., Tabata, M., Nishii, K., Matsuo, K., Hotta, K., Kozuki, T., Aoe, M., Kiura, K., Ueoka, H., and Tanimoto, M. (2005) Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer, Clin Cancer Res 11, 1219–1225.

    Article  PubMed  CAS  Google Scholar 

  55. Tsou, J. A., Galler, J. S., Wali, A., Ye, W., Siegmund, K. D., Groshen, S., Laird, P. W., Turla, S., Koss, M. N., Pass, H. I., and Laird-Offringa, I. A. (2007) DNA methylation profile of 28 potential marker loci in malignant mesothelioma, Lung cancer 58, 220–230.

    Article  PubMed  Google Scholar 

  56. Toyooka, S., Pass, H. I., Shivapurkar, N., Fukuyama, Y., Maruyama, R., Toyooka, K. O., Gilcrease, M., Farinas, A., Minna, J. D., and Gazdar, A. F. (2001) Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma, Cancer Res 61, 5727–5730.

    PubMed  CAS  Google Scholar 

  57. Fischer, J. R., Ohnmacht, U., Rieger, N., Zemaitis, M., Stoffregen, C., Kostrzewa, M., Buchholz, E., Manegold, C., and Lahm, H. (2006) Promoter methylation of RASSF1A, RARbeta and DAPK predict poor prognosis of patients with malignant mesothelioma, Lung cancer 54, 109–116.

    Article  PubMed  Google Scholar 

  58. Issa, J. P., and Kantarjian, H. M. (2009) Targeting DNA methylation, Clin Cancer Res 15, 3938–3946.

    Article  PubMed  CAS  Google Scholar 

  59. Silverman, L. R., Demakos, E. P., Peterson, B. L., Kornblith, A. B., Holland, J. C., Odchimar-Reissig, R., Stone, R. M., Nelson, D., Powell, B. L., DeCastro, C. M., Ellerton, J., Larson, R. A., Schiffer, C. A., and Holland, J. F. (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B, J Clin Oncol 20, 2429–2440.

    Article  PubMed  CAS  Google Scholar 

  60. Kantarjian, H., Issa, J. P., Rosenfeld, C. S., Bennett, J. M., Albitar, M., DiPersio, J., Klimek, V., Slack, J., de Castro, C., Ravandi, F., Helmer, R., 3rd, Shen, L., Nimer, S. D., Leavitt, R., Raza, A., and Saba, H. (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study, Cancer 106, 1794–1803.

    Article  PubMed  CAS  Google Scholar 

  61. Schrump, D. S., Fischette, M. R., Nguyen, D. M., Zhao, M., Li, X., Kunst, T. F., Hancox, A., Hong, J. A., Chen, G. A., Pishchik, V., Figg, W. D., Murgo, A. J., and Steinberg, S. M. (2006) Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura, Clin Cancer Res 12, 5777–5785.

    Article  PubMed  CAS  Google Scholar 

  62. Momparler, R. L., and Ayoub, J. (2001) Potential of 5-aza-2′-deoxycytidine (Decitabine) a potent inhibitor of DNA methylation for therapy of advanced non-small cell lung cancer, Lung cancer 34 Suppl 4, S111–115.

    Article  PubMed  Google Scholar 

  63. Shen, L., Kantarjian, H., Guo, Y., Lin, E., Shan, J., Huang, X., Berry, D., Ahmed, S., Zhu, W., Pierce, S., Kondo, Y., Oki, Y., Jelinek, J., Saba, H., Estey, E., and Issa, J. P. (2010) DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes, J Clin Oncol 28, 605–613.

    Article  PubMed  CAS  Google Scholar 

  64. Appleton, K., Mackay, H. J., Judson, I., Plumb, J. A., McCormick, C., Strathdee, G., Lee, C., Barrett, S., Reade, S., Jadayel, D., Tang, A., Bellenger, K., Mackay, L., Setanoians, A., Schatzlein, A., Twelves, C., Kaye, S. B., and Brown, R. (2007) Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors, J Clin Oncol 25, 4603–4609.

    Article  PubMed  CAS  Google Scholar 

  65. Plumb, J. A., Strathdee, G., Sludden, J., Kaye, S. B., and Brown, R. (2000) Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter, Cancer Res 60, 6039–6044.

    PubMed  CAS  Google Scholar 

  66. Varambally, S., Dhanasekaran, S. M., Zhou, M., Barrette, T. R., Kumar-Sinha, C., Sanda, M. G., Ghosh, D., Pienta, K. J., Sewalt, R. G., Otte, A. P., Rubin, M. A., and Chinnaiyan, A. M. (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer, Nature 419, 624–629.

    Article  PubMed  CAS  Google Scholar 

  67. Kikuchi, J., Kinoshita, I., Shimizu, Y., Kikuchi, E., Konishi, J., Oizumi, S., Kaga, K., Matsuno, Y., Nishimura, M., and Dosaka-Akita, H. (2010) Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance, Cancer 116, 3015–3024.

    Article  PubMed  CAS  Google Scholar 

  68. Barlesi, F., Giaccone, G., Gallegos-Ruiz, M. I., Loundou, A., Span, S. W., Lefesvre, P., Kruyt, F. A., and Rodriguez, J. A. (2007) Global histone modifications predict prognosis of resected non small-cell lung cancer, J Clin Oncol 25, 4358–4364.

    Article  PubMed  Google Scholar 

  69. Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., McDermott, U., Azizian, N., Zou, L., Fischbach, M. A., Wong, K. K., Brandstetter, K., Wittner, B., Ramaswamy, S., Classon, M., and Settleman, J. (2010) A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations, Cell 141, 69–80.

    Article  PubMed  CAS  Google Scholar 

  70. Juergens R. A., Vendetti F., Coleman B., Sebree R. S., Rudek M. A., Belinsky S., Brock M., Herman J., Baylin S., Rudin C. M. (2009) Interim analysis of a phase II trial of 5-azacitidine (5AC) and entinostat (SNDX-275) in relapsed advanced lung cancer (NSCLC), J Clin Oncol 27:15s, abstr 8055.

    Google Scholar 

  71. Ley, T. J., Ding, L., Walter, M. J., McLellan, M. D., Lamprecht, T., Larson, D. E., Kandoth, C., Payton, J. E., Baty, J., Welch, J., Harris, C. C., Lichti, C. F., Townsend, R. R., Fulton, R. S., Dooling, D. J., Koboldt, D. C., Schmidt, H., Zhang, Q., Osborne, J. R., Lin, L., O’Laughlin, M., McMichael, J. F., Delehaunty, K. D., McGrath, S. D., Fulton, L. A., Magrini, V. J., Vickery, T. L., Hundal, J., Cook, L. L., Conyers, J. J., Swift, G. W., Reed, J. P., Alldredge, P. A., Wylie, T., Walker, J., Kalicki, J., Watson, M. A., Heath, S., Shannon, W. D., Varghese, N., Nagarajan, R., Westervelt, P., Tomasson, M. H., Link, D. C., Graubert, T. A., DiPersio, J. F., Mardis, E. R., and Wilson, R. K. (2010) DNMT3A mutations in acute myeloid leukemia, N Engl J Med 363, 2424–2433.

    Article  PubMed  CAS  Google Scholar 

  72. Morin, R. D., Johnson, N. A., Severson, T. M., Mungall, A. J., An, J., Goya, R., Paul, J. E., Boyle, M., Woolcock, B. W., Kuchenbauer, F., Yap, D., Humphries, R. K., Griffith, O. L., Shah, S., Zhu, H., Kimbara, M., Shashkin, P., Charlot, J. F., Tcherpakov, M., Corbett, R., Tam, A., Varhol, R., Smailus, D., Moksa, M., Zhao, Y., Delaney, A., Qian, H., Birol, I., Schein, J., Moore, R., Holt, R., Horsman, D. E., Connors, J. M., Jones, S., Aparicio, S., Hirst, M., Gascoyne, R. D., and Marra, M. A. (2010) Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin, Nat Genet 42, 181–185.

    Article  PubMed  CAS  Google Scholar 

  73. Kim, J. S., Kim, J. W., Han, J., Shim, Y. M., Park, J., and Kim, D. H. (2006) Cohypermethylation of p16 and FHIT promoters as a prognostic factor of recurrence in surgically resected stage I non-small cell lung cancer, Cancer Res 66, 4049–4054.

    Article  PubMed  CAS  Google Scholar 

  74. Yanagawa, N., Tamura, G., Oizumi, H., Takahashi, N., Shimazaki, Y., and Motoyama, T. (2003) Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers, Cancer Sci 94, 589–592.

    Article  PubMed  CAS  Google Scholar 

  75. Helmbold, P., Lahtz, C., Herpel, E., Schnabel, P. A., and Dammann, R. H. (2009) Frequent hypermethylation of RASSF1A tumour suppressor gene promoter and presence of Merkel cell polyomavirus in small cell lung cancer, Eur J Cancer 45, 2207–2211.

    Article  PubMed  CAS  Google Scholar 

  76. Shivapurkar, N., Stastny, V., Suzuki, M., Wistuba, II, Li, L., Zheng, Y., Feng, Z., Hol, B., Prinsen, C., Thunnissen, F. B., and Gazdar, A. F. (2007) Application of a methylation gene panel by quantitative PCR for lung cancers, Cancer Lett 247, 56–71.

    Article  PubMed  CAS  Google Scholar 

  77. Hawes, S. E., Stern, J. E., Feng, Q., Wiens, L. W., Rasey, J. S., Lu, H., Kiviat, N. B., and Vesselle, H. (2010) DNA hypermethylation of tumors from non-small cell lung cancer (NSCLC) patients is associated with gender and histologic type, Lung cancer 69, 172–179.

    Article  PubMed  Google Scholar 

  78. Buckingham, L., Penfield Faber, L., Kim, A., Liptay, M., Barger, C., Basu, S., Fidler, M., Walters, K., Bonomi, P., and Coon, J. (2010) PTEN, RASSF1 and DAPK site-specific hypermethylation and outcome in surgically treated stage I and II nonsmall cell lung cancer patients, Int J Cancer 126, 1630–1639.

    PubMed  CAS  Google Scholar 

  79. Palmisano, W. A., Crume, K. P., Grimes, M. J., Winters, S. A., Toyota, M., Esteller, M., Joste, N., Baylin, S. B., and Belinsky, S. A. (2003) Aberrant promoter methylation of the transcription factor genes PAX5 alpha and beta in human cancers, Cancer Res 63, 4620–4625.

    PubMed  CAS  Google Scholar 

  80. Koga, T., Takeshita, M., Yano, T., Maehara, Y., and Sueishi, K. (2010) CHFR hypermethylation and EGFR mutation are mutually exclusive and exhibit contrastive clinical backgrounds and outcomes in non-small cell lung cancer, Int J Cancer 128, 1009–1017.

    Article  Google Scholar 

  81. Mizuno, K., Osada, H., Konishi, H., Tatematsu, Y., Yatabe, Y., Mitsudomi, T., Fujii, Y., and Takahashi, T. (2002) Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers, Oncogene 21, 2328–2333.

    Article  PubMed  CAS  Google Scholar 

  82. Zochbauer-Muller, S., Fong, K. M., Maitra, A., Lam, S., Geradts, J., Ashfaq, R., Virmani, A. K., Milchgrub, S., Gazdar, A. F., and Minna, J. D. (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.

    PubMed  CAS  Google Scholar 

  83. Toyooka, S., Toyooka, K. O., Maruyama, R., Virmani, A. K., Girard, L., Miyajima, K., Harada, K., Ariyoshi, Y., Takahashi, T., Sugio, K., Brambilla, E., Gilcrease, M., Minna, J. D., and Gazdar, A. F. (2001) DNA methylation profiles of lung tumors, Mol Cancer Ther 1, 61–67.

    PubMed  CAS  Google Scholar 

  84. Marsit, C. J., Kim, D. H., Liu, M., Hinds, P. W., Wiencke, J. K., Nelson, H. H., and Kelsey, K. T. (2005) Hypermethylation of RASSF1A and BLU tumor suppressor genes in non-small cell lung cancer: implications for tobacco smoking during adolescence, Int J Cancer 114, 219–223.

    Article  PubMed  CAS  Google Scholar 

  85. Agathanggelou, A., Dallol, A., Zochbauer-Muller, S., Morrissey, C., Honorio, S., Hesson, L., Martinsson, T., Fong, K. M., Kuo, M. J., Yuen, P. W., Maher, E. R., Minna, J. D., and Latif, F. (2003) Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers, Oncogene 22, 1580–1588.

    Article  PubMed  CAS  Google Scholar 

  86. Zochbauer-Muller, S., Fong, K. M., Virmani, A. K., Geradts, J., Gazdar, A. F., and Minna, J. D. (2001) Aberrant promoter methylation of multiple genes in non-small cell lung cancers, Cancer Res 61, 249–255.

    PubMed  CAS  Google Scholar 

  87. Marsit, C. J., Liu, M., Nelson, H. H., Posner, M., Suzuki, M., and Kelsey, K. T. (2004) Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival, Oncogene 23, 1000–1004.

    Article  PubMed  CAS  Google Scholar 

  88. Lee, M. N., Tseng, R. C., Hsu, H. S., Chen, J. Y., Tzao, C., Ho, W. L., and Wang, Y. C. (2007) Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer, Clin Cancer Res 13, 832–838.

    Article  PubMed  CAS  Google Scholar 

  89. Hopkins-Donaldson, S., Ziegler, A., Kurtz, S., Bigosch, C., Kandioler, D., Ludwig, C., Zangemeister-Wittke, U., and Stahel, R. (2003) Silencing of death receptor and caspase-8 expression in small cell lung carcinoma cell lines and tumors by DNA methylation, Cell death and differentiation 10, 356–364.

    Article  PubMed  CAS  Google Scholar 

  90. Shivapurkar, N., Toyooka, S., Eby, M. T., Huang, C. X., Sathyanarayana, U. G., Cunningham, H. T., Reddy, J. L., Brambilla, E., Takahashi, T., Minna, J. D., Chaudhary, P. M., and Gazdar, A. F. (2002) Differential inactivation of caspase-8 in lung cancers, Cancer Biol Ther 1, 65–69.

    Article  PubMed  CAS  Google Scholar 

  91. Virmani, A., Rathi, A., Sugio, K., Sathyanarayana, U. G., Toyooka, S., Kischel, F. C., Tonk, V., Padar, A., Takahashi, T., Roth, J. A., Euhus, D. M., Minna, J. D., and Gazdar, A. F. (2003) Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer, Int J Cancer 106, 198–204.

    Article  PubMed  CAS  Google Scholar 

  92. Marsit, C. J., Zheng, S., Aldape, K., Hinds, P. W., Nelson, H. H., Wiencke, J. K., and Kelsey, K. T. (2005) PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration, Human pathology 36, 768–776.

    Article  PubMed  CAS  Google Scholar 

  93. Dammann, R., Takahashi, T., and Pfeifer, G. P. (2001) The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas, Oncogene 20, 3563–3567.

    Article  PubMed  CAS  Google Scholar 

  94. Lai, J. C., Cheng, Y. W., Chiou, H. L., Wu, M. F., Chen, C. Y., and Lee, H. (2005) Gender difference in estrogen receptor alpha promoter hypermethylation and its prognostic value in non-small cell lung cancer, Int J Cancer 117, 974–980.

    Article  PubMed  CAS  Google Scholar 

  95. He, B., You, L., Uematsu, K., Zang, K., Xu, Z., Lee, A. Y., Costello, J. F., McCormick, F., and Jablons, D. M. (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer, Proc Natl Acad Sci U S A 100, 14133–14138.

    Article  PubMed  CAS  Google Scholar 

  96. Dammann, R., Strunnikova, M., Schagdarsurengin, U., Rastetter, M., Papritz, M., Hattenhorst, U. E., Hofmann, H. S., Silber, R. E., Burdach, S., and Hansen, G. (2005) CpG island methylation and expression of tumour-associated genes in lung carcinoma, Eur J Cancer 41, 1223–1236.

    Article  PubMed  CAS  Google Scholar 

  97. Kikuchi, S., Yamada, D., Fukami, T., Maruyama, T., Ito, A., Asamura, H., Matsuno, Y., Onizuka, M., and Murakami, Y. (2006) Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma, Cancer 106, 1751–1758.

    Article  PubMed  CAS  Google Scholar 

  98. Heller, G., Fong, K. M., Girard, L., Seidl, S., End-Pfutzenreuter, A., Lang, G., Gazdar, A. F., Minna, J. D., Zielinski, C. C., and Zochbauer-Muller, S. (2006) Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas, Oncogene 25, 959–968.

    Article  PubMed  CAS  Google Scholar 

  99. Marsit, C. J., Houseman, E. A., Christensen, B. C., Eddy, K., Bueno, R., Sugarbaker, D. J., Nelson, H. H., Karagas, M. R., and Kelsey, K. T. (2006) Examination of a CpG island methylator phenotype and implications of methylation profiles in solid tumors, Cancer Res 66, 10621–10629.

    Article  PubMed  CAS  Google Scholar 

  100. Suzuki, M., Wada, H., Yoshino, M., Tian, L., Shigematsu, H., Suzuki, H., Alaa, M., Tamura, H., Fujiwara, T., Nagato, K., Motohashi, S., Moriya, Y., Hoshino, H., Yoshida, S., Shibuya, K., Hiroshima, K., Nakatani, Y., and Yoshino, I. (2010) Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling, Ann Surg Oncol 17, 878–888.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yutaka Kondo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Shinjo, K., Kondo, Y. (2012). Clinical Implications of Epigenetic Alterations in Human Thoracic Malignancies: Epigenetic Alterations in Lung Cancer. In: Dumitrescu, R., Verma, M. (eds) Cancer Epigenetics. Methods in Molecular Biology, vol 863. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-612-8_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-612-8_13

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-611-1

  • Online ISBN: 978-1-61779-612-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics