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[Cancer Research 60, 5954-5958, November 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Predicting Lung Cancer by Detecting Aberrant Promoter Methylation in Sputum1

William A. Palmisano, Kevin K. Divine, Geno Saccomanno, Frank D. Gilliland, Stephen B. Baylin, James G. Herman and Steven A. Belinsky2

Lovelace Respiratory Research Institute, Lung Cancer Program, Albuquerque, New Mexico 87185 [W. A. P., K. K. D., S. A. B.]; St. Mary’s Hospital, Grand Junction, Colorado 81501 [G. S.]; Department of Preventive Medicine, Division of Occupational and Environmental Health, University of Southern California, Los Angeles, California 90033 [F. D. G.]; and Johns Hopkins University Medical Institutions, The Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland 21231 [S. B. B., J. G. H.]

Despite the promise of using DNA markers for the early detection of cancer, none has proven universally applicable to the most common and lethal forms of human malignancy. Lung carcinoma, the leading cause of tumor-related death, is a key example of a cancer for which mortality could be greatly reduced through the development of sensitive molecular markers detectable at the earliest stages of disease. By increasing the sensitivity of a PCR approach to detect methylated DNA sequences, we now demonstrate that aberrant methylation of the p16 and/or O6-methylguanine-DNA methyltransferase promoters can be detected in DNA from sputum in 100% of patients with squamous cell lung carcinoma up to 3 years before clinical diagnosis. Moreover, the prevalence of these markers in sputum from cancer-free, high-risk subjects approximates lifetime risk for lung cancer. The use of aberrant gene methylation as a molecular marker system seems to offer a potentially powerful approach to population-based screening for the detection of lung cancer, and possibly the other common forms of human cancer.




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G. F. V. Woude, G. J. Kelloff, R. W. Ruddon, H.-M. Koo, C. C. Sigman, J. C. Barrett, R. W. Day, A. P. Dicker, R. S. Kerbel, D. R. Parkinson, et al.
Reanalysis of Cancer Drugs: Old Drugs, New Tricks
Clin. Cancer Res., June 1, 2004; 10(11): 3897 - 3907.
[Full Text] [PDF]

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 ANN INTERN MEDHome page
L. L. Humphrey, S. Teutsch, and M. Johnson
Lung Cancer Screening with Sputum Cytologic Examination, Chest Radiography, and Computed Tomography: An Update for the U.S. Preventive Services Task Force
Ann Intern Med, May 4, 2004; 140(9): 740 - 753.
[Abstract] [Full Text] [PDF]

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 ChestHome page
J. G. Herman
Epigenetics in Lung Cancer: Focus on Progression and Early Lesions
Chest, May 1, 2004; 125(5_suppl): 119S - 122S.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
O. Topaloglu, M. O. Hoque, Y. Tokumaru, J. Lee, E. Ratovitski, D. Sidransky, and C.-s. Moon
Detection of Promoter Hypermethylation of Multiple Genes in the Tumor and Bronchoalveolar Lavage of Patients with Lung Cancer
Clin. Cancer Res., April 1, 2004; 10(7): 2284 - 2288.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
D. B. Douglas, Y. Akiyama, H. Carraway, S. A. Belinsky, M. Esteller, E. Gabrielson, S. Weitzman, T. Williams, J. G. Herman, and S. B. Baylin
Hypermethylation of a Small CpGuanine-Rich Region Correlates with Loss of Activator Protein-2{alpha} Expression during Progression of Breast Cancer
Cancer Res., March 1, 2004; 64(5): 1611 - 1620.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
S. E. Cottrell, J. Distler, N. S. Goodman, S. H. Mooney, A. Kluth, A. Olek, I. Schwope, R. Tetzner, H. Ziebarth, and K. Berlin
A real-time PCR assay for DNA-methylation using methylation-specific blockers
Nucleic Acids Res., January 13, 2004; 32(1): e10 - e10.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
R. Krassenstein, E. Sauter, E. Dulaimi, C. Battagli, H. Ehya, A. Klein-Szanto, and P. Cairns
Detection of Breast Cancer in Nipple Aspirate Fluid by CpG Island Hypermethylation
Clin. Cancer Res., January 1, 2004; 10(1): 28 - 32.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
C. Battagli, R. G. Uzzo, E. Dulaimi, I. Ibanez de Caceres, R. Krassenstein, T. Al-Saleem, R. E. Greenberg, and P. Cairns
Promoter Hypermethylation of Tumor Suppressor Genes in Urine from Kidney Cancer Patients
Cancer Res., December 15, 2003; 63(24): 8695 - 8699.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
L. Kopelovich, J. A. Crowell, and J. R. Fay
The Epigenome as a Target for Cancer Chemoprevention
J Natl Cancer Inst, December 3, 2003; 95(23): 1747 - 1757.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
Y. Liu, Q. An, L. Li, D. Zhang, J. Huang, X. Feng, S. Cheng, and Y. Gao
Hypermethylation of p16INK4a in Chinese lung cancer patients: biological and clinical implications
Carcinogenesis, December 1, 2003; 24(12): 1897 - 1901.
[Abstract] [Full Text] [PDF]

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 NEJMHome page
J. G. Herman and S. B. Baylin
Gene Silencing in Cancer in Association with Promoter Hypermethylation
N. Engl. J. Med., November 20, 2003; 349(21): 2042 - 2054.
[Full Text] [PDF]

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 Cancer Res.Home page
M. Z. Fang, Y. Wang, N. Ai, Z. Hou, Y. Sun, H. Lu, W. Welsh, and C. S. Yang
Tea Polyphenol (-)-Epigallocatechin-3-Gallate Inhibits DNA Methyltransferase and Reactivates Methylation-Silenced Genes in Cancer Cell Lines
Cancer Res., November 15, 2003; 63(22): 7563 - 7570.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
A. McWilliams, J. Mayo, S. MacDonald, J. C. leRiche, B. Palcic, E. Szabo, and S. Lam
Lung Cancer Screening: A Different Paradigm
Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1167 - 1173.
[Abstract] [Full Text] [PDF]

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 JCOHome page
G. Sozzi, D. Conte, M. Leon, R. Cirincione, L. Roz, C. Ratcliffe, E. Roz, N. Cirenei, M. Bellomi, G. Pelosi, et al.
Quantification of Free Circulating DNA As a Diagnostic Marker in Lung Cancer
J. Clin. Oncol., November 1, 2003; 21(21): 3902 - 3908.
[Abstract] [Full Text] [PDF]

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 J. Clin. Pathol.Home page
F B J M Thunnissen
Sputum examination for early detection of lung cancer
J. Clin. Pathol., November 1, 2003; 56(11): 805 - 810.
[Abstract] [Full Text] [PDF]

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 Cancer Epidemiol. Biomarkers Prev.Home page
S. A. Prindiville, T. Byers, F. R. Hirsch, W. A. Franklin, Y. E. Miller, K. O. Vu, H. J. Wolf, A. E. Baron, K. R. Shroyer, C. Zeng, et al.
Sputum Cytological Atypia as a Predictor of Incident Lung Cancer in a Cohort of Heavy Smokers with Airflow Obstruction
Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 987 - 993.
[Abstract] [Full Text] [PDF]

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 Ann. Surg. Oncol.Home page
M. G. House, I. I. Wistuba, P. Argani, M. Guo, R. D. Schulick, R. H. Hruban, J. G. Herman, and A. Maitra
Progression of Gene Hypermethylation in Gallstone Disease Leading to Gallbladder Cancer
Ann. Surg. Oncol., October 1, 2003; 10(8): 882 - 889.
[Abstract] [Full Text] [PDF]

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 Toxicol SciHome page
R. E. Watson, G. M. Curtin, D. J. Doolittle, and J. I. Goodman
Progressive Alterations in Global and GC-Rich DNA Methylation during Tumorigenesis
Toxicol. Sci., October 1, 2003; 75(2): 289 - 299.
[Abstract] [Full Text] [PDF]

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 ThoraxHome page
K M Fong, Y Sekido, A F Gazdar, and J D Minna
Lung cancer * 9: Molecular biology of lung cancer: clinical implications
Thorax, October 1, 2003; 58(10): 892 - 900.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
L. C. Pulling, K. K. Divine, D. M. Klinge, F. D. Gilliland, T. Kang, A. G. Schwartz, T. J. Bocklage, and S. A. Belinsky
Promoter Hypermethylation of the O6-Methylguanine-DNA Methyltransferase Gene: More Common in Lung Adenocarcinomas from Never-Smokers than Smokers and Associated with Tumor Progression
Cancer Res., August 15, 2003; 63(16): 4842 - 4848.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
W. A. Palmisano, K. P. Crume, M. J. Grimes, S. A. Winters, M. Toyota, M. Esteller, N. Joste, S. B. Baylin, and S. A. Belinsky
Aberrant Promoter Methylation of the Transcription Factor Genes PAX5 {alpha} and {beta} in Human Cancers
Cancer Res., August 1, 2003; 63(15): 4620 - 4625.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
S. A. Ahrendt, Y. Hu, M. Buta, M. P. McDermott, N. Benoit, S. C. Yang, L. Wu, and D. Sidransky
p53 Mutations and Survival in Stage I Non-Small-Cell Lung Cancer: Results of a Prospective Study
J Natl Cancer Inst, July 2, 2003; 95(13): 961 - 970.
[Abstract] [Full Text] [PDF]

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 JCOHome page
J. M. Kurie
Cyclin D1 Expression in the Field of Exposure: Another Piece in the Molecular Auerbach Puzzle
J. Clin. Oncol., June 1, 2003; 21(11): 2056 - 2058.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
M. Jeanmart, S. Lantuejoul, F. Fievet, D. Moro, N. Sturm, C. Brambilla, and E. Brambilla
Value of Immunohistochemical Markers in Preinvasive Bronchial Lesions in Risk Assessment of Lung Cancer
Clin. Cancer Res., June 1, 2003; 9(6): 2195 - 2203.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
L. Zhang, W. Lu, X. Miao, D. Xing, W. Tan, and D. Lin
Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma
Carcinogenesis, June 1, 2003; 24(6): 1039 - 1044.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. Milutinovic, Q. Zhuang, A. Niveleau, and M. Szyf
Epigenomic Stress Response. KNOCKDOWN OF DNA METHYLTRANSFERASE 1 TRIGGERS AN INTRA-S-PHASE ARREST OF DNA REPLICATION AND INDUCTION OF STRESS RESPONSE GENES
J. Biol. Chem., April 18, 2003; 278(17): 14985 - 14995.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
M. G. House, M. Guo, C. Iacobuzio-Donahue, and J. G. Herman
Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas
Carcinogenesis, February 1, 2003; 24(2): 193 - 198.
[Abstract] [Full Text] [PDF]

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 JAMAHome page
P. J. Mahadevia, L. A. Fleisher, K. D. Frick, J. Eng, S. N. Goodman, and N. R. Powe
Lung Cancer Screening With Helical Computed Tomography in Older Adult Smokers: A Decision and Cost-effectiveness Analysis
JAMA, January 15, 2003; 289(3): 313 - 322.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
C. Brambilla, F. Fievet, M. Jeanmart, F. de Fraipont, S. Lantuejoul, V. Frappat, G. Ferretti, P.Y. Brichon, and D. Moro-Sibilot
Early detection of lung cancer: role of biomarkers
Eur. Respir. J., January 1, 2003; 21(39_suppl): 36S - 44s.
[Abstract] [Full Text] [PDF]

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 ChestHome page
P. B. Bach, D. E. Niewoehner, and W. C. Black
Screening for Lung Cancer: The Guidelines
Chest, January 1, 2003; 123(1_suppl): 83S - 88S.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
E. C. Chan, S. Y. Lam, K. W. Tsang, B. Lam, J. C. M. Ho, K. H. Fu, W. K. Lam, and Y. L. Kwong
Aberrant Promoter Methylation in Chinese Patients with Non-Small Cell Lung Cancer: Patterns in Primary Tumors and Potential Diagnostic Application in Bronchoalevolar Lavage
Clin. Cancer Res., December 1, 2002; 8(12): 3741 - 3746.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
A. Bearzatto, D. Conte, M. Frattini, N. Zaffaroni, F. Andriani, D. Balestra, L. Tavecchio, M. G. Daidone, and G. Sozzi
p16INK4A Hypermethylation Detected by Fluorescent Methylation-specific PCR in Plasmas from Non-Small Cell Lung Cancer
Clin. Cancer Res., December 1, 2002; 8(12): 3782 - 3787.
[Abstract] [Full Text] [PDF]

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 ThoraxHome page
G E Goodman
Lung cancer * 1: Prevention of lung cancer
Thorax, November 1, 2002; 57(11): 994 - 999.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
C. Plass
Cancer epigenomics
Hum. Mol. Genet., October 1, 2002; 11(20): 2479 - 2488.
[Abstract] [Full Text] [PDF]

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 The OncologistHome page
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]


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