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Aberrant methylation in non-small cell lung cancer

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Abstract

The potential of tumor suppressor genes (TSGs) to serve as clinical markers for disease detection, progression, and therapeutic response was evaluated by conducting a comprehensive review of the English-language scientific literature on aberrant promoter methylation of TSGs in non-small cell lung cancer (NSCLC). Genome-wide hypermethylation and silencing of TSGs are common features of cancer cells. Aberrant promoter methylation has been found in NSCLC, and research is now focused on the identification of specific genes that exhibit differential expression levels based on the methylation state. Aberrant methylation in NSCLC is observed in the early development of cancer and can be detected in DNA circulating in the blood or isolated from sputum. Therefore, methylation assays offer the promise of a noninvasive test for detecting cancer. In addition, the identification of cancer-specific epigenetic changes may be useful for molecular classification and disease stratification. Hence, the detection of cancerspecific methylation changes heralds an exciting new era in the diagnosis of cancer, its prognosis, and therapeutic responsiveness, and warrants further investigation in NSCLC.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.

    Article  PubMed  Google Scholar 

  2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  3. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–9826.

    Article  CAS  PubMed  Google Scholar 

  4. Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001;61:3225–3229.

    CAS  PubMed  Google Scholar 

  5. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002;3:415–428.

    Article  CAS  PubMed  Google Scholar 

  6. Suzuki M, Shigematsu H, Nakajima T, Kubo R, Motohashi S, Sekine Y, et al. Synchronous alterations of Wnt and epidermal growth factor receptor signaling pathways through aberrant methylation and mutation in non small cell lung cancer. Clin Cancer Res 2007;13:6087–6092.

    Article  CAS  PubMed  Google Scholar 

  7. Shivapurkar N, Toyooka S, Toyooka KO, Reddy J, Miyajima K, Suzuki M, et al. Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types. Int J Cancer 2004;109:786–792.

    Article  CAS  PubMed  Google Scholar 

  8. Toyooka S, Toyooka KO, Miyajima K, Reddy JL, Toyota M, Sathyanarayana UG, et al. Epigenetic down-regulation of deathassociated protein kinase in lung cancers. Clin Cancer Res 2003;9:3034–3041.

    CAS  PubMed  Google Scholar 

  9. Suzuki M, Shigematsu H, Iizasa T, Hiroshima K, Nakatani Y, Minna JD, et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer 2006;106:2200–2207.

    Article  CAS  PubMed  Google Scholar 

  10. Chen H, Suzuki M, Nakamura Y, Ohira M, Ando S, Iida T, et al. Aberrant methylation of FBN2 in human non-small cell lung cancer. Lung Cancer 2005;50:43–49.

    Article  PubMed  Google Scholar 

  11. Suzuki M, Sunaga N, Shames DS, Toyooka S, Gazdar AF, Minna JD. RNA interference-mediated knockdown of DNA methyltransferase 1 leads to promoter demethylation and gene reexpression in human lung and breast cancer cells. Cancer Res 2004;64:3137–3143.

    Article  CAS  PubMed  Google Scholar 

  12. Suzuki M, Shigematsu H, Takahashi T, Shivapurkar N, Sathyanarayana UG, Iizasa T, et al. Aberrant methylation of Reprimo in lung cancer. Lung Cancer 2005;47:309–314.

    Article  PubMed  Google Scholar 

  13. Osada H, Tatematsu Y, Yatabe Y, Nakagawa T, Konishi H, Harano T, et al. Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers. Oncogene 2002;21:2418–2424.

    Article  CAS  PubMed  Google Scholar 

  14. Vuillemenot BR, Pulling LC, Palmisano WA, Hutt JA, Belinsky SA. Carcinogen exposure differentially modulates RAR-beta promoter hypermethylation, an early and frequent event in mouse lung carcinogenesis. Carcinogenesis 2004;25:623–629.

    Article  CAS  PubMed  Google Scholar 

  15. Rhee I, Bachman KE, Park BH, Jair KW, Yen RW, Schuebel KE, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 2002;416:552–556.

    Article  CAS  PubMed  Google Scholar 

  16. Robert MF, Morin S, Beaulieu N, Gauthier F, Chute IC, Barsalou A, et al. DNMT1 is required to maintain CpG methylation and aberrant gene silencing in human cancer cells. Nat Genet 2003;33:61–65.

    Article  CAS  PubMed  Google Scholar 

  17. Cottrell SE. Molecular diagnostic applications of DNA methylation technology. Clin Biochem 2004;37:595–604.

    Article  CAS  PubMed  Google Scholar 

  18. Cottrell SE, Laird PW. Sensitive detection of DNA methylation. Ann N Y Acad Sci 2003;983:120–130.

    Article  CAS  PubMed  Google Scholar 

  19. Seng TJ, Currey N, Cooper WA, Lee CS, Chan C, Horvath L, et al. DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma. Br J Cancer 2008;99:375–382.

    Article  CAS  PubMed  Google Scholar 

  20. Suzuki M, Mohamed S, Nakajima T, Kubo R, Tian L, Fujiwara T, et al. Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis. Int J Oncol 2008;33:113–119.

    CAS  PubMed  Google Scholar 

  21. Kim DS, Kim MJ, Lee JY, Kim YZ, Kim EJ, Park JY. Aberrant methylation of E-cadherin and H-cadherin genes in nonsmall cell lung cancer and its relation to clinicopathologic features. Cancer 2007;110:2785–2792.

    Article  CAS  PubMed  Google Scholar 

  22. Yanagawa N, Tamura G, Oizumi H, Kanauchi N, Endoh M, Sadahiro M, et al. Promoter hypermethylation of RASSF1A and RUNX3 genes as an independent prognostic prediction marker in surgically resected non-small cell lung cancers. Lung Cancer 2007;58:131–138.

    Article  PubMed  Google Scholar 

  23. Gu J, Berman D, Lu C, Wistuba II, Roth JA, Frazier M, et al. Aberrant promoter methylation profile and association with survival in patients with non-small cell lung cancer. Clin Cancer Res 2006;12:7329–7338.

    Article  CAS  PubMed  Google Scholar 

  24. Ota N, Kawakami K, Okuda T, Takehara A, Hiranuma C, Oyama K, et al. Prognostic significance of p16(INK4a) hypermethylation in non-small cell lung cancer is evident by quantitative DNA methylation analysis. Anticancer Res 2006;26:3729–3732.

    CAS  PubMed  Google Scholar 

  25. Zhang Z, Tan S, Zhang L. Prognostic value of apoptosis-associated speck-like protein containing a CARD gene promoter methylation in resectable non-small-cell lung cancer. Clin Lung Cancer 2006;8:62–65.

    Article  CAS  PubMed  Google Scholar 

  26. Kim JS, Kim JW, Han J, Shim YM, Park J, Kim DH. Cohypermethylation of p16 and FHIT promoters as a prognostic factor of recurrence in surgically resected stage I non-small cell lung cancer. Cancer Res 2006;66:4049–4054.

    Article  CAS  PubMed  Google Scholar 

  27. Hsu HS, Wen CK, Tang YA, Lin RK, Li WY, Hsu WH, et al. Promoter hypermethylation is the predominant mechanism in hMLH1 and hMSH2 deregulation and is a poor prognostic factor in nonsmoking lung cancer. Clin Cancer Res 2005;11:5410–5416.

    Article  CAS  PubMed  Google Scholar 

  28. Lai JC, Cheng YW, Chiou HL, Wu MF, Chen CY, Lee H. Gender difference in estrogen receptor alpha promoter hypermethylation and its prognostic value in non-small cell lung cancer. Int J Cancer 2005;117:974–980.

    Article  CAS  PubMed  Google Scholar 

  29. Wang J, Lee JJ, Wang L, Liu DD, Lu C, Fan YH, et al. Value of p16INK4a and RASSF1A promoter hypermethylation in prognosis of patients with resectable non-small cell lung cancer. Clin Cancer Res 2004;10:6119–6125.

    Article  CAS  PubMed  Google Scholar 

  30. Maruyama R, Sugio K, Yoshino I, Maehara Y, Gazdar AF. Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma. Cancer 2004;100:1472–1477.

    Article  CAS  PubMed  Google Scholar 

  31. Brabender J, Usadel H, Metzger R, Schneider PM, Park J, Salonga D, et al. Quantitative O(6)-methylguanine DNA methyltransferase methylation analysis in curatively resected non-small cell lung cancer: associations with clinical outcome. Clin Cancer Res 2003;9:223–227.

    CAS  PubMed  Google Scholar 

  32. Chang YS, Wang L, Liu D, Mao L, Hong WK, Khuri FR, et al. Correlation between insulin-like growth factor-binding protein-3 promoter methylation and prognosis of patients with stage I nonsmall cell lung cancer. Clin Cancer Res 2002;8:3669–3675.

    CAS  PubMed  Google Scholar 

  33. Usadel H, Brabender J, Danenberg KD, Jeronimo C, Harden S, Engles J, et al. Quantitative adenomatous polyposis coli promoter methylation analysis in tumor tissue, serum, and plasma DNA of patients with lung cancer. Cancer Res 2002;62:371–375.

    CAS  PubMed  Google Scholar 

  34. Brabender J, Usadel H, Danenberg KD, Metzger R, Schneider PM, Lord RV, et al. Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival. Oncogene 2001;20:3528–3532.

    Article  CAS  PubMed  Google Scholar 

  35. Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC, et al. p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res 2001;61:3419–3424.

    CAS  PubMed  Google Scholar 

  36. Tang X, Khuri FR, Lee JJ, Kemp BL, Liu D, Hong WK, et al. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst 2000;92:1511–1516.

    Article  CAS  PubMed  Google Scholar 

  37. Brock MV, Hooker CM, Ota-Machida E, Han Y, Guo M, Ames S, et al. DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 2008;358:1118–1128.

    Article  CAS  PubMed  Google Scholar 

  38. Fischer JR, Ohnmacht U, Rieger N, Zemaitis M, Stoffregen C, Manegold C, et al. Prognostic significance of RASSF1A promoter methylation on survival of non-small cell lung cancer patients treated with gemcitabine. Lung Cancer 2007;56:115–123.

    Article  PubMed  Google Scholar 

  39. Ramirez JL, Rosell R, Taron M, Sanchez-Ronco M, Alberola V, de Las Penas R, et al. 14-3-3sigma methylation in pretreatment serum circulating DNA of cisplatin-plus-gemcitabine-treated advanced non-small-cell lung cancer patients predicts survival: The Spanish Lung Cancer Group. J Clin Oncol 2005;23:9105–9112.

    Article  CAS  PubMed  Google Scholar 

  40. Belinsky SA, Palmisano WA, Gilliland FD, Crooks LA, Divine KK, Winters SA, et al. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res 2002;62:2370–2377.

    CAS  PubMed  Google Scholar 

  41. Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 2000;60:5954–5958.

    CAS  PubMed  Google Scholar 

  42. Baryshnikova E, Destro A, Infante MV, Cavuto S, Cariboni U, Alloisio M, et al. Molecular alterations in spontaneous sputum of cancer-free heavy smokers: results from a large screening program. Clin Cancer Res 2008;14:1913–1919.

    Article  CAS  PubMed  Google Scholar 

  43. Hsu HS, Chen TP, Wen CK, Hung CH, Chen CY, Chen JT, et al. Multiple genetic and epigenetic biomarkers for lung cancer detection in cytologically negative sputum and a nested case-control study for risk assessment. J Pathol 2007;213:412–419.

    Article  CAS  PubMed  Google Scholar 

  44. Shivapurkar N, Stastny V, Xie Y, Prinsen C, Frenkel E, Czerniak B, et al. Differential methylation of a short CpG-rich sequence within exon 1 of TCF21 gene: a promising cancer biomarker assay. Cancer Epidemiol Biomarkers Prev 2008;17:995–1000.

    Article  CAS  PubMed  Google Scholar 

  45. Tan SH, Ida H, Lau QC, Goh BC, Chieng WS, Loh M, et al. Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3. Oncol Rep 2007;18:1225–1230.

    CAS  PubMed  Google Scholar 

  46. Ulivi P, Zoli W, Calistri D, Fabbri F, Tesei A, Rosetti M, et al. p16INK4A and CDH13 hypermethylation in tumor and serum of non-small cell lung cancer patients. J Cell Physiol 2006;206:611–615.

    Article  CAS  PubMed  Google Scholar 

  47. Fujiwara K, Fujimoto N, Tabata M, Nishii K, Matsuo K, Hotta K, et al. Identification of epigenetic aberrant promoter methylation in serum DNA is useful for early detection of lung cancer. Clin Cancer Res 2005;11:1219–1225.

    Article  CAS  PubMed  Google Scholar 

  48. Sigalotti L, Fratta E, Coral S, Cortini E, Covre A, Nicolay HJ, et al. Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. J Cell Physiol 2007;212:330–344.

    Article  CAS  PubMed  Google Scholar 

  49. Nam JS, Ino Y, Kanai Y, Sakamoto M, Hirohashi S. 5-aza-2′-deoxycytidine restores the E-cadherin system in E-cadherinsilenced cancer cells and reduces cancer metastasis. Clin Exp Metastasis 2004;21:49–56.

    Article  CAS  PubMed  Google Scholar 

  50. Kassis ES, Zhao M, Hong JA, Chen GA, Nguyen DM, Schrump DS. Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. J Thorac Cardiovasc Surg 2006;131:298–306.

    Article  CAS  PubMed  Google Scholar 

  51. Lin RK, Hsu CH, Wang YC. Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells. Anticancer Drugs 2007;18:1157–1164.

    Article  CAS  PubMed  Google Scholar 

  52. Momparler RL, Ayoub J. Potential of 5-aza-2′-deoxycytidine (Decitabine), a potent inhibitor of DNA methylation for therapy of advanced non-small cell lung cancer. Lung Cancer 2001;34suppl 4:S111–S115.

    Article  PubMed  Google Scholar 

  53. Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, et al. Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clin Cancer Res 2006;12:5777–5785.

    Article  CAS  PubMed  Google Scholar 

  54. Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, et al. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol 2007;18:1529–1538.

    Article  CAS  PubMed  Google Scholar 

  55. Shukeir N, Pakneshan P, Chen G, Szyf M, Rabbani SA. Alteration of the methylation status of tumor-promoting genes decreases prostate cancer cell invasiveness and tumorigenesis in vitro and in vivo. Cancer Res 2006;66:9202–9210.

    Article  CAS  PubMed  Google Scholar 

  56. Esquela-Kerscher A, Slack FJ. Oncomirs — microRNAs with a role in cancer. Nat Rev Cancer 2006;6:259–269.

    Article  CAS  PubMed  Google Scholar 

  57. Kim VN. MicroRNA biogenesis: coordinated cropping and dicing. Nat Rev Mol Cell Biol 2005;6:376–385.

    Article  CAS  PubMed  Google Scholar 

  58. Huang JC, Babak T, Corson TW, Chua G, Khan S, Gallie BL, et al. Using expression profiling data to identify human microRNA targets. Nat Methods 2007;4:1045–1049.

    Article  CAS  PubMed  Google Scholar 

  59. Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, et al. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res 2007;67:1419–1423.

    Article  CAS  PubMed  Google Scholar 

  60. Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 2007;67:1424–1429.

    Article  CAS  PubMed  Google Scholar 

  61. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A 2007;104:15805–15810.

    Article  CAS  PubMed  Google Scholar 

  62. Kagan J, Srivastava S, Barker PE, Belinsky SA, Cairns P. Towards clinical application of methylated DNA sequences as cancer biomarkers: A joint NCI’s EDRN and NIST Workshop on standards, methods, assays, reagents and tools. Cancer Res 2007;67:4545–4549.

    Article  CAS  PubMed  Google Scholar 

  63. Li LC, Carroll PR, Dahiya R. Epigenetic changes in prostate cancer: implication for diagnosis and treatment. J Natl Cancer Inst 2005;97:103–115.

    Article  CAS  PubMed  Google Scholar 

  64. Shivapurkar N, Takahashi T, Reddy J, Zheng Y, Stastny V, Collins R, et al. Presence of simian virus 40 DNA sequences in human lymphoid and hematopoietic malignancies and their relationship to aberrant promoter methylation of multiple genes. Cancer Res 2004;64:3757–3760.

    Article  CAS  PubMed  Google Scholar 

  65. Chim CS, Fung TK, Cheung WC, Liang R, Kwong YL. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak/STAT pathway. Blood 2004;103:4630–4635.

    Article  CAS  PubMed  Google Scholar 

  66. Beck S, Rakyan VK. The methylome: approaches for global DNA methylation profiling. Trends Genet 2008;24:231–237.

    Article  CAS  PubMed  Google Scholar 

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Suzuki, M., Yoshino, I. Aberrant methylation in non-small cell lung cancer. Surg Today 40, 602–607 (2010). https://doi.org/10.1007/s00595-009-4094-6

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