Skip to main content
Log in

Wif1 hypermethylation as unfavorable prognosis of non-small cell lung cancers with EGFR mutation

  • Published:
Molecules and Cells

Abstract

Lung cancer is a leading cause of cancer-related mortality across the world and tobacco smoking is the major risk factor. The Wnt signaling pathway is known to be involved in smoke-induced tumorigenesis in the lung. Promoter hypermethylation of Wnt inhibitory factor 1 (Wif1) has become a common event in a number of human tumors. Using a methylation-specific PCR, hypermethylation of the Wif1 gene promoter was evaluated in 139 primary nonsmall cell lung cancers (NSCLCs) and its correlation with clinicopathological and prognostic parameters was evaluated. Methylation of Wif1 was observed in 47.5% and 20.9% of neoplastic and adjacent normal lung tissues, respectively. Its methylation rate tended to be higher in stage I than stages II-IIIA. Results of Kaplan-Meier analysis showed no significant difference in overall survival according to Wif1 methylation status. However, Wif1 methylation showed an association with unfavorable prognosis of adenocarcinoma (AC) patients with EGFR mutation. According to our current findings, Wif1 promoter methylation is an early, frequent event as an epigenetic field manner and could be considered as a useful prognostic marker for AC patients with EGFR mutation. Further investigation into the therapeutic potential of this finding is warranted.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

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

    PubMed  CAS  Google Scholar 

  • Gazdar, A.F., Shigematsu, H., and Herz, J. (2004). Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers? Trends Mol. Med. 10, 481–486.

    Article  PubMed  CAS  Google Scholar 

  • Guo, M., House, M.G., Hooker, C., Han, Y., Heath, E., Gabrielson, E., Yang, S.C., Baylin, S.B., Herman, J.G., and Brock, M.V. (2004). Promoter hypermethylation of resected bronchial margins: a field defect of changes? Clin. Cancer Res. 10, 5131–5136.

    CAS  Google Scholar 

  • Hu, T., and Li, C. (2010). Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol. Cancer 9, 236–242.

    Article  PubMed  Google Scholar 

  • Jee, S.H., Samet, J.M., Ohrr, H., Kim, J.H., and Kim, I.S. (2004). Smoking and cancer risk in Korean men and women. Cancer Cases Control 15, 341–348.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Kerr, K.M., Galler, J.S., Hagen, J.A., Laird, P.W., and Laird-Offringa, I.A. (2007). The role of DNA methylation in the development and progression in lung adenocarcinoma. Disease Marker 23, 5–30.

    Article  CAS  Google Scholar 

  • Kim, D.S., Cha, S.I., Lee, J.H., Lee, Y.M., Choi, J.E., Kim, M.J., Lim, J.S., Lee, E.B., Kim, C.H., Park, T.I., et al. (2007). Aberrant DNA methylation profiles of non-small cell lung cancers in a Korean population. Lung Cancer 58, 1–6.

    Article  PubMed  Google Scholar 

  • Konigshoff, M., and Eickelberg, O. (2010). WNT signaling in lung disease. Am. J. Respir. Cell. Mol. Biol. 42, 21–31.

    Article  PubMed  Google Scholar 

  • Lee, S.M., Park, J.Y., and Kim, D.S. (2012). Methylation of TMEFF2 gene in tissue and serum DNA from patients with non-small cell lung cancer. Mol. Cells 34, 171–176.

    Article  PubMed  CAS  Google Scholar 

  • Lemjabbar-Alaoui, H., Dasari, V., Sidhu, S., Mengistab, A., Finkbeiner, W., Gallup, M., and Basbaum, C. (2006). Wnt and hedgehog are critical mediators of cigarette smoke-induced lung cancer. PLoS One 1, 1–11.

    Article  Google Scholar 

  • Licchesi, J.D.F., Westra, W.H., Hooker, C.M., Machida, E.O., Baylin, S.B., and Herman, J.G. (2008). Epignetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis 29, 895–904.

    Article  PubMed  CAS  Google Scholar 

  • Liu, F., Killian, J.K., Yang, M., Walker, R.L., Hong, J.A., Zhang, M., Davis, S., Zhang, Y., Hussain, M., Xi, S., et al. (2010). Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene 29, 3650–3664.

    Article  PubMed  CAS  Google Scholar 

  • Mazieres, J., He, B., You, L., Xu, Z., Lee, A.Y., Mikami, I., Reguart, N., Rosell, R., McCormick, F., and Jablons, D.M. (2004). Wnt inhibitory factor is silenced by promoter hypermethylation in human lung cancer. Cancer Res. 64, 717–720.

    Article  Google Scholar 

  • Mazieres, J., He, B., You, L., Xu, Z., and Jablons, D.M. (2005). Wnt signaling in lung cancer. Cancer Lett. 222, 1–10.

    Article  PubMed  CAS  Google Scholar 

  • Minna, J.D., Roth, J.A., and Gazdar, A.F. (2002). Focus on lung cancer. Cancer Cell 1, 49–52.

    Article  PubMed  CAS  Google Scholar 

  • Na, Y.K., Lee, S.M., Hong, H.S., Kim, J.B., Park, J.Y., and Kim, D.S. (2010). Hypermethylation of growth arrest DNA-damage inducible gene 45 in non-small cell lung cancer and its relationship with clinicopathologic features. Mol. Cells 30, 89–92.

    Article  PubMed  CAS  Google Scholar 

  • Na, Y.K., Lee, S.M., Kim, D.S., and Park, J.Y. (2012). Promoter methylation of Wnt antagonist DKK1 gene and prognostic value in Korean patients with non-small cell lung cancers. Cancer Biomarkers 12, 73–79.

    PubMed  CAS  Google Scholar 

  • Nakamura, H., Kawasaki, N., Taguchi, M., and Kabasawa, K. (2006). Survival impact of epidermal growth factor receptor overexpression in patients with non-small cell lung cancer: a meta-analysis. Thorax 61, 140–145.

    Article  PubMed  CAS  Google Scholar 

  • Ohtsuka, K., Ohnishi, H., Furuyashiki, G., Nogami, H., Koshiishi, Y., Ooide, A., Matsushima, S., Watanabe, T., and Goya, T. (2006). Clinico-pathological and biological significance of tyrosine kinase domain gene mutations and overexpression of epidermal growth factor receptor for lung adenocarcinoma. J. Thorac. Oncol. 8, 787–795.

    Article  Google Scholar 

  • Paul, S., and Dey, A. (2008). Wnt signaling and cancer development: therapeutic implication. Neoplasma 55, 165–176.

    PubMed  CAS  Google Scholar 

  • Rubin, J.S., Barshishat-Kupper, M., Feroze-Merzoug, F., and Xi, Z.F. (2006). Secreted WNT antagonists as tumor suppressors: pro and con. Front. Biosci. 11, 2093–105.

    Article  PubMed  CAS  Google Scholar 

  • Sharm, 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  Google Scholar 

  • Tang, M., Torres-Lanzas, J., Lopez-Rios, F., Esteller, M., and Sanchez-Cespedes, M. (2006). Wnt signaling promoter hyperemthylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung. Int. J. Cancer 119, 2603–2606.

    Article  PubMed  CAS  Google Scholar 

  • Toyooka, S., Toyook, K.O., Maruyama, R., Virmani, A.K., Girard, L., Miyajima, K., Harada, K., Ariyoshi, Y., Takahashi, T., Sugio, K., et al. (2001). DNA methylation profiles of lung tumors. Mol. Cancer Ther. 1, 61–67.

    PubMed  CAS  Google Scholar 

  • Toyooka, S., Maruyama, R., and Toyooka, K.O. (2003). Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer. Int. J. Cancer 103, 153–160.

    Article  PubMed  CAS  Google Scholar 

  • Van Scoyk, M., Randall, J., Sergew, A., Williams, L.M., Tennis, M., and Winn, R.A. (2008). Wnt signaling pathway and lung disease. Transl. Res. 151, 175–180.

    Article  PubMed  Google Scholar 

  • Wang, R., Ahmed, J., Wang, G., Hassan, I., Strulovici-Barel, Y., Hackett, N.R., and Crystal, R.G. (2011). Down-regulation of the canonical Wnt β-catenin pathway in the airway epithelium of healthy smokers and smokers with COPD. PLoS One 6, e14793.

    Article  PubMed  CAS  Google Scholar 

  • Ying, Y., and Tao, Q. (2009). Epigenetic disruption of the WNT/β-catenin signaling pathway in human cancers. Epigenetics 4, 307–312.

    Article  PubMed  CAS  Google Scholar 

  • Yoshino, M., Suzuki, M., Tian, L., Moriya, Y., Hoshino, H., Okamoto, T., Yoshida, S., Shibuya, K., and Yoshino, I. (2009). Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers. Int. J. Oncol. 35, 1201–1209.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, J., Wang, Y., Duan, J., Bai, H., Wang, Z., Wei, L., Zhao, J., Zhou, M., Wang, S., Yang, L., et al. (2012). DNA methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer. J. Exp. Clin. Cancer Res. 31, 80–88.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jae Yong Park or Dong Sun Kim.

About this article

Cite this article

Lee, S.M., Park, J.Y. & Kim, D.S. Wif1 hypermethylation as unfavorable prognosis of non-small cell lung cancers with EGFR mutation. Mol Cells 36, 69–73 (2013). https://doi.org/10.1007/s10059-013-0060-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10059-013-0060-7

Keywords

Navigation