Aberrant Promoter Methylation of Multiple Genes in Non-Small Cell Lung Cancers

Immunology

Aberrant Promoter Methylation of Multiple Genes in Non-Small Cell Lung Cancers¹

Sabine Zöchbauer-Müller, Kwun M. Fong, Arvind K. Virmani, Joseph Geradts, Adi F. Gazdar and John D. Minna²

Hamon Center for Therapeutic Oncology Research [S. Z-M., A. K. V., A. F. G., J. D. M.], Departments of Pathology [A. F. G.], Internal Medicine [J. D. M.], and Pharmacology [J. D. M.], The University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390-8593; Department of Thoracic Medicine, The Prince Charles Hospital, Chermside, Brisbane 4032, Australia [K. M. F.]; and Nuffield Department of Pathology & Bacteriology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom [J. G.]

Aberrant methylation of CpG islands acquired in tumor cellsin promoter regions is one method for loss of gene function.We determined the frequency of aberrant promoter methylation(referred to as methylation) of the genes retinoic acid receptorß-2 (RARß), tissue inhibitor of metalloproteinase3 (TIMP-3), p16^I^N^K4^a, O⁶-methylguanine-DNA-methyltransferase (MGMT),death-associated protein kinase (DAPK), E-cadherin (ECAD), p14^A^R^F,and glutathione S-transferase P1 (GSTP1) in 107 resected primarynon-small cell lung cancers (NSCLCs) and in 104 corresponding nonmalignantlung tissues by methylation-specific PCR. Methylation in thetumor samples was detected in 40% for RARß, 26% for TIMP-3,25% for p16^I^N^K4^a, 21% for MGMT, 19% for DAPK, 18% for ECAD,8% for p14^A^R^F, and 7% for GSTP1, whereas it was not seen inthe vast majority of the corresponding nonmalignant tissues.Moreover, p16^I^N^K4^a methylation was correlated with loss of p16^INK4aexpression by immunohistochemistry. A total of 82% of the NSCLCshad methylation of at least one of these genes; 37% of the NSCLCshad one gene methylated, 22% of the NSCLCs had two genes methylated,13% of the NSCLCs had three genes methylated, 8% of the NSCLCshad four genes methylated, and 2% of the NSCLCs had five genes methylated.Methylation of these genes was correlated with some clinicopathologicalcharacteristics of the patients. In comparing the methylationpatterns of tumors and nonmalignant lung tissues from the samepatients, there were many discordancies where the genes methylated innonmalignant tissues were not methylated in the corresponding tumors.This suggests that the methylation was occurring as a preneoplasticchange. We conclude that these findings confirm in a large samplethat methylation is a frequent event in NSCLC, can also occurin smoking-damaged nonmalignant lung tissues, and may be themost common mechanism to inactivate cancer-related genes inNSCLC.

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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

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[Abstract] [Full Text] [PDF]

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Clin. Cancer Res., May 15, 2004; 10(10): 3479 - 3489.
[Abstract] [Full Text] [PDF]

N. Reesink-Peters, G. B. A. Wisman, C. Jeronimo, C. Y. Tokumaru, Y. Cohen, S. M. Dong, H. G. Klip, H. J. Buikema, A. J.H. Suurmeijer, H. Hollema, et al.
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Mol. Cancer Res., May 1, 2004; 2(5): 289 - 295.
[Abstract] [Full Text] [PDF]

T. Takahashi, N. Shivapurkar, J. Reddy, H. Shigematsu, K. Miyajima, M. Suzuki, S. Toyooka, S. Zochbauer-Muller, J. Drach, G. Parikh, et al.
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Clin. Cancer Res., May 1, 2004; 10(9): 2928 - 2935.
[Abstract] [Full Text] [PDF]

J. G. Herman
Epigenetics in Lung Cancer: Focus on Progression and Early Lesions
Chest, May 1, 2004; 125(5_suppl): 119S - 122S.
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H. Kim, G.-L. Xu, A. C. Borczuk, S. Busch, J. Filmus, M. Capurro, J. S. Brody, J. Lange, J. M. D'Armiento, P. B. Rothman, et al.
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Am. J. Respir. Cell Mol. Biol., December 1, 2003; 29(6): 694 - 701.
[Abstract] [Full Text] [PDF]

P. Gonzalez-Gomez, M. J. Bello, M. E. Alonso, J. Lomas, D. Arjona, J. M. d. Campos, J. Vaquero, A. Isla, L. Lassaletta, M. Gutierrez, et al.
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Clin. Cancer Res., November 15, 2003; 9(15): 5601 - 5606.
[Abstract] [Full Text] [PDF]

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Thorax, October 1, 2003; 58(10): 892 - 900.
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S. Lee, H. J. Lee, J.-H. Kim, H.-S. Lee, J. J. Jang, and G. H. Kang
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Am. J. Pathol., October 1, 2003; 163(4): 1371 - 1378.
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T. Ohira, R. M. Gemmill, K. Ferguson, S. Kusy, J. Roche, E. Brambilla, C. Zeng, A. Baron, L. Bemis, P. Erickson, et al.
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PNAS, September 2, 2003; 100(18): 10429 - 10434.
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L. C. Pulling, K. K. Divine, D. M. Klinge, F. D. Gilliland, T. Kang, A. G. Schwartz, T. J. Bocklage, and S. A. Belinsky
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M. V. Brock, M. Gou, Y. Akiyama, A. Muller, T.-T. Wu, E. Montgomery, M. Deasel, P. Germonpre, L. Rubinson, R. F. Heitmiller, et al.
Prognostic Importance of Promoter Hypermethylation of Multiple Genes in Esophageal Adenocarcinoma
Clin. Cancer Res., August 1, 2003; 9(8): 2912 - 2919.
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S. Toyooka, K. O. Toyooka, K. Miyajima, J. L. Reddy, M. Toyota, U. G. Sathyanarayana, A. Padar, M. S. Tockman, S. Lam, N. Shivapurkar, et al.
Epigenetic Down-Regulation of Death-associated Protein Kinase in Lung Cancers
Clin. Cancer Res., August 1, 2003; 9(8): 3034 - 3041.
[Abstract] [Full Text] [PDF]

T. Kuroki, F. Trapasso, S. Yendamuri, A. Matsuyama, H. Alder, M. Mori, and C. M. Croce
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Cancer Res., July 1, 2003; 63(13): 3724 - 3728.
[Abstract] [Full Text] [PDF]

D.-H. Kim, J. S. Kim, Y.-I. Ji, Y. M. Shim, H. Kim, J. Han, and J. Park
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Cancer Res., July 1, 2003; 63(13): 3743 - 3746.
[Abstract] [Full Text] [PDF]

S. V. Harden, Y. Tokumaru, W. H. Westra, S. Goodman, S. A. Ahrendt, S. C. Yang, and D. Sidransky
Gene Promoter Hypermethylation in Tumors and Lymph Nodes of Stage I Lung Cancer Patients
Clin. Cancer Res., April 1, 2003; 9(4): 1370 - 1375.
[Abstract] [Full Text] [PDF]

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J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1367 - 1373.
[Abstract] [Full Text] [PDF]

J. Brabender, H. Usadel, R. Metzger, P. M. Schneider, J. Park, D. Salonga, D. D. Tsao-Wei, S. Groshen, R. V. Lord, N. Takebe, et al.
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[Abstract] [Full Text] [PDF]

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Eur. Respir. J., January 1, 2003; 21(39_suppl): 36S - 44s.
[Abstract] [Full Text] [PDF]

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M. E. Reid, A. J. Duffield-Lillico, L. Garland, B. W. Turnbull, L. C. Clark, and J. R. Marshall
Selenium Supplementation and Lung Cancer Incidence: An Update of the Nutritional Prevention of Cancer Trial
Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1285 - 1291.
[Abstract] [Full Text] [PDF]

S. Zochbauer-Muller, J. D. Minna, and A. F. Gazdar
Aberrant DNA Methylation in Lung Cancer: Biological and Clinical Implications
Oncologist, October 1, 2002; 7(5): 451 - 457.
[Abstract] [Full Text] [PDF]

K. O. Toyooka, S. Toyooka, A. Maitra, Q. Feng, N. C. Kiviat, A. Smith, J. D. Minna, R. Ashfaq, and A. F. Gazdar
Establishment and Validation of Real-Time Polymerase Chain Reaction Method for CDH1 Promoter Methylation
Am. J. Pathol., August 1, 2002; 161(2): 629 - 634.
[Abstract] [Full Text] [PDF]

O. Straume, J. Smeds, R. Kumar, K. Hemminki, and L. A. Akslen
Significant Impact of Promoter Hypermethylation and the 540 C>T Polymorphism of CDKN2A in Cutaneous Melanoma of the Vertical Growth Phase
Am. J. Pathol., July 1, 2002; 161(1): 229 - 237.
[Abstract] [Full Text] [PDF]

Y. Tomizawa, T. Kohno, H. Kondo, A. Otsuka, M. Nishioka, T. Niki, T. Yamada, A. Maeshima, K. Yoshimura, R. Saito, et al.
Clinicopathological Significance of Epigenetic Inactivation of RASSF1A at 3p21.3 in Stage I Lung Adenocarcinoma
Clin. Cancer Res., July 1, 2002; 8(7): 2362 - 2368.
[Abstract] [Full Text] [PDF]

F.R. Hirsch, D.T. Merrick, and W.A. Franklin
Role of biomarkers for early detection of lung cancer and chemoprevention
Eur. Respir. J., June 1, 2002; 19(6): 1151 - 1158.
[Abstract] [Full Text] [PDF]

J.-C. Soria, H.-Y. Lee, J. I. Lee, L. Wang, J.-P. Issa, B. L. Kemp, D. D. Liu, J. M. Kurie, L. Mao, and F. R. Khuri
Lack of PTEN Expression in Non-Small Cell Lung Cancer Could Be Related to Promoter Methylation
Clin. Cancer Res., May 1, 2002; 8(5): 1178 - 1184.
[Abstract] [Full Text] [PDF]

S. A. Belinsky, W. A. Palmisano, F. D. Gilliland, L. A. Crooks, K. K. Divine, S. A. Winters, M. J. Grimes, H. J. Harms, C. S. Tellez, T. M. Smith, et al.
Aberrant Promoter Methylation in Bronchial Epithelium and Sputum from Current and Former Smokers
Cancer Res., April 1, 2002; 62(8): 2370 - 2377.
[Abstract] [Full Text] [PDF]

A. K. Virmani, J. A. Tsou, K. D. Siegmund, L. Y. C. Shen, T. I. Long, P. W. Laird, A. F. Gazdar, and I. A. Laird-Offringa
Hierarchical Clustering of Lung Cancer Cell Lines Using DNA Methylation Markers
Cancer Epidemiol. Biomarkers Prev., March 1, 2002; 11(3): 291 - 297.
[Abstract] [Full Text] [PDF]

M. W. Y. Chan, L. W. Chan, N. L. S. Tang, J. H. M. Tong, K. W. Lo, T. L. Lee, H. Y. Cheung, W. S. Wong, P. S. F. Chan, F. M. M. Lai, et al.
Hypermethylation of Multiple Genes in Tumor Tissues and Voided Urine in Urinary Bladder Cancer Patients
Clin. Cancer Res., February 1, 2002; 8(2): 464 - 470.
[Abstract] [Full Text] [PDF]

R. Maruyama, S. Toyooka, K. O. Toyooka, A. K. Virmani, S. Zochbauer-Muller, A. J. Farinas, J. D. Minna, J. McConnell, E. P. Frenkel, and A. F. Gazdar
Aberrant Promoter Methylation Profile of Prostate Cancers and Its Relationship to Clinicopathological Features
Clin. Cancer Res., February 1, 2002; 8(2): 514 - 519.
[Abstract] [Full Text] [PDF]

J.-C. Soria, M. Rodriguez, D. D. Liu, J. J. Lee, W. Ki Hong, and L. Mao
Aberrant Promoter Methylation of Multiple Genes in Bronchial Brush Samples from Former Cigarette Smokers
Cancer Res., January 1, 2002; 62(2): 351 - 355.
[Abstract] [Full Text] [PDF]

B. Halmos, C. S. Huettner, O. Kocher, K. Ferenczi, D. D. Karp, and D. G. Tenen
Down-Regulation and Antiproliferative Role of C/EBP{alpha} in Lung Cancer
Cancer Res., January 1, 2002; 62(2): 528 - 534.
[Abstract] [Full Text] [PDF]

T. Ueki, M. Toyota, H. Skinner, K. M. Walter, C. J. Yeo, J.-P. J. Issa, R. H. Hruban, and M. Goggins
Identification and Characterization of Differentially Methylated CpG Islands in Pancreatic Carcinoma
Cancer Res., December 1, 2001; 61(23): 8540 - 8546.
[Abstract] [Full Text] [PDF]

R. Maruyama, S. Toyooka, K. O. Toyooka, K. Harada, A. K. Virmani, S. Zochbauer-Muller, A. J. Farinas, F. Vakar-Lopez, J. D. Minna, A. Sagalowsky, et al.
Aberrant Promoter Methylation Profile of Bladder Cancer and Its Relationship to Clinicopathological Features
Cancer Res., December 1, 2001; 61(24): 8659 - 8663.
[Abstract] [Full Text] [PDF]

Y. Tomizawa, Y. Sekido, M. Kondo, B. Gao, J. Yokota, J. Roche, H. Drabkin, M. I. Lerman, A. F. Gazdar, and J. D. Minna
Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B
PNAS, November 20, 2001; 98(24): 13954 - 13959.
[Abstract] [Full Text] [PDF]

Y. Du, T. Carling, W. Fang, Z. Piao, J.-C. Sheu, and S. Huang
Hypermethylation in Human Cancers of the RIZ1 Tumor Suppressor Gene, a Member of a Histone/Protein Methyltransferase Superfamily
Cancer Res., November 1, 2001; 61(22): 8094 - 8099.
[Abstract] [Full Text] [PDF]

S. Toyooka, K. O. Toyooka, R. Maruyama, A. K. Virmani, L. Girard, K. Miyajima, K. Harada, Y. Ariyoshi, T. Takahashi, K. Sugio, et al.
DNA Methylation Profiles of Lung Tumors
Mol. Cancer Ther., November 1, 2001; 1(1): 61 - 67.
[Abstract] [Full Text] [PDF]

C. Nguyen, G. Liang, T. T. Nguyen, D. Tsao-Wei, S. Groshen, M. Lubbert, J.-H. Zhou, W. F. Benedict, and P. A. Jones
Susceptibility of Nonpromoter CpG Islands to De Novo Methylation in Normal and Neoplastic Cells
J Natl Cancer Inst, October 3, 2001; 93(19): 1465 - 1472.
[Abstract] [Full Text] [PDF]

A. K. Virmani, A. Rathi, U. G. Sathyanarayana, A. Padar, C. X. Huang, H. T. Cunnigham, A. J. Farinas, S. Milchgrub, D. M. Euhus, M. Gilcrease, et al.
Aberrant Methylation of the Adenomatous Polyposis Coli (APC) Gene Promoter 1A in Breast and Lung Carcinomas
Clin. Cancer Res., July 1, 2001; 7(7): 1998 - 2004.
[Abstract] [Full Text] [PDF]

D. G. Burbee, E. Forgacs, S. Zochbauer-Muller, L. Shivakumar, K. Fong, B. Gao, D. Randle, M. Kondo, A. Virmani, S. Bader, et al.
Epigenetic Inactivation of RASSF1A in Lung and Breast Cancers and Malignant Phenotype Suppression
J Natl Cancer Inst, May 2, 2001; 93(9): 691 - 699.
[Abstract] [Full Text] [PDF]

S. Zöchbauer-Müller, K. M. Fong, A. Maitra, S. Lam, J. Geradts, R. Ashfaq, A. K. Virmani, S. Milchgrub, A. F. Gazdar, and J. D. Minna
5' CpG Island Methylation of the FHIT Gene Is Correlated with Loss of Gene Expression in Lung and Breast Cancer
Cancer Res., May 1, 2001; 61(9): 3581 - 3585.
[Abstract] [Full Text]