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[Cancer Research 59, 67-70, January 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 67-70, January 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Detection of Aberrant Promoter Hypermethylation of Tumor Suppressor Genes in Serum DNA from Non-Small Cell Lung Cancer Patients1

Manel Esteller, Montserrat Sanchez-Cespedes, Rafael Rosell, David Sidransky, Stephen B. Baylin and James G. Herman2

Tumor Biology, The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [M. E., S. B. B., J. G. H.]; and Department of Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research [M. S-C., D. S.], and Medical Oncology Service [R. R.], Hospital Germans Trias i Pujol, Badalona, Spain

Recent evidence suggests that tumor cells may release DNA into the circulation, which is enriched in the serum and plasma, allowing detection of ras and p53 mutations and microsatellite alterations in the serum DNA of cancer patients. We examined whether aberrant DNA methylation might also be found in the serum of patients with non-small cell lung cancer. We tested 22 patients with non-small cell lung cancer using methylation-specific PCR, searching for promoter hypermethylation of the tumor suppressor gene p16, the putative metastasis suppressor gene death-associated protein kinase, the detoxification gene glutathione S-transferase P1, and the DNA repair gene O6-methylguanine-DNA-methyltransferase. Aberrant methylation of at least one of these genes was detected in 15 of 22 (68%) NSCLC tumors but not in any paired normal lung tissue. In these primary tumors with methylation, 11 of 15 (73%) samples also had abnormal methylated DNA in the matched serum samples. Moreover, none of the sera from patients with tumors not demonstrating methylation was positive. Abnormal promoter methylation in serum DNA was found in all tumor stages. Although these results need to be confirmed in larger studies and in other tumor types, detection of aberrant promoter hypermethylation of cancer-related genes in serum may be useful for cancer diagnosis or the detection of recurrence.




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G. Gifford, J. Paul, P. A. Vasey, S. B. Kaye, and R. Brown
The Acquisition of hMLH1 Methylation in Plasma DNA after Chemotherapy Predicts Poor Survival for Ovarian Cancer Patients
Clin. Cancer Res., July 1, 2004; 10(13): 4420 - 4426.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
L. C. Pulling, B. R. Vuillemenot, J. A. Hutt, T. R. Devereux, and S. A. Belinsky
Aberrant Promoter Hypermethylation of the Death-Associated Protein Kinase Gene Is Early and Frequent in Murine Lung Tumors Induced by Cigarette Smoke and Tobacco Carcinogens
Cancer Res., June 1, 2004; 64(11): 3844 - 3848.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. W. Park, R. S. Kerbel, G. J. Kelloff, J. C. Barrett, B. A. Chabner, D. R. Parkinson, J. Peck, R. W. Ruddon, C. C. Sigman, and D. J. Slamon
Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development
Clin. Cancer Res., June 1, 2004; 10(11): 3885 - 3896.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
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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 J. Mol. Diagn.Home page
Y.-H. Su, M. Wang, D. E. Brenner, A. Ng, H. Melkonyan, S. Umansky, S. Syngal, and T. M. Block
Human Urine Contains Small, 150 to 250 Nucleotide-Sized, Soluble DNA Derived from the Circulation and May Be Useful in the Detection of Colorectal Cancer
J. Mol. Diagn., May 1, 2004; 6(2): 101 - 107.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
P. Pakneshan, B. Tetu, and S. A. Rabbani
Demethylation of Urokinase Promoter as a Prognostic Marker in Patients with Breast Carcinoma
Clin. Cancer Res., May 1, 2004; 10(9): 3035 - 3041.
[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
E. Dulaimi, R. G. Uzzo, R. E. Greenberg, T. Al-Saleem, and P. Cairns
Detection of Bladder Cancer in Urine by a Tumor Suppressor Gene Hypermethylation Panel
Clin. Cancer Res., March 15, 2004; 10(6): 1887 - 1893.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
K. Terasawa, S. Sagae, M. Toyota, K. Tsukada, K. Ogi, A. Satoh, H. Mita, K. Imai, T. Tokino, and R. Kudo
Epigenetic Inactivation of TMS1/ASC in Ovarian Cancer
Clin. Cancer Res., March 15, 2004; 10(6): 2000 - 2006.
[Abstract] [Full Text] [PDF]

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 J. Mol. Diagn.Home page
A. M. Marchevsky, J. A. Tsou, and I. A. Laird-Offringa
Classification of Individual Lung Cancer Cell Lines Based on DNA Methylation Markers: Use of Linear Discriminant Analysis and Artificial Neural Networks
J. Mol. Diagn., February 1, 2004; 6(1): 28 - 36.
[Abstract] [Full Text]

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 JCOHome page
D. G. Pfister, D. H. Johnson, C. G. Azzoli, W. Sause, T. J. Smith, S. Baker Jr, J. Olak, D. Stover, J. R. Strawn, A. T. Turrisi, et al.
American Society of Clinical Oncology Treatment of Unresectable Non-Small-Cell Lung Cancer Guideline: Update 2003
J. Clin. Oncol., January 15, 2004; 22(2): 330 - 353.
[Full Text] [PDF]

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 Clin. Cancer Res.Home page
A. Widschwendter, H. M. Muller, H. Fiegl, L. Ivarsson, A. Wiedemair, E. Muller-Holzner, G. Goebel, C. Marth, and M. Widschwendter
DNA Methylation in Serum and Tumors of Cervical Cancer Patients
Clin. Cancer Res., January 15, 2004; 10(2): 565 - 571.
[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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 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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 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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 JCOHome page
P. A. Bunn Jr
Early Detection of Lung Cancer Using Serum RNA or DNA Markers: Ready for """Prime Time""" or for Validation?
J. Clin. Oncol., November 1, 2003; 21(21): 3891 - 3893.
[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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 CarcinogenesisHome page
P. E. Jackson, S.-Y. Kuang, J.-B. Wang, P. T. Strickland, A. Munoz, T. W. Kensler, G.-S. Qian, and J. D. Groopman
Prospective detection of codon 249 mutations in plasma of hepatocellular carcinoma patients
Carcinogenesis, October 1, 2003; 24(10): 1657 - 1663.
[Abstract] [Full Text] [PDF]

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 Nucleic Acids ResHome page
P. Hou, M. Ji, C. Ge, J. Shen, S. Li, N. He, and Z. Lu
Detection of methylation of human p16Ink4a gene 5'-CpG islands by electrochemical method coupled with linker-PCR
Nucleic Acids Res., August 15, 2003; 31(16): e92 - e92.
[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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 Clin. Cancer Res.Home page
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]

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 Mol. Pathol.Home page
B M Ryan, F Lefort, R McManus, J Daly, P W N Keeling, D G Weir, and D Kelleher
A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up
Mol. Pathol., June 1, 2003; 56(3): 172 - 179.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
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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 Clin. Cancer Res.Home page
C. Balana, J. L. Ramirez, M. Taron, Y. Roussos, A. Ariza, R. Ballester, C. Sarries, P. Mendez, J. J. Sanchez, and R. Rosell
O6-methyl-guanine-DNA methyltransferase Methylation in Serum and Tumor DNA Predicts Response to 1,3-Bis(2-Chloroethyl)-1-Nitrosourea but not to Temozolamide Plus Cisplatin in Glioblastoma Multiforme
Clin. Cancer Res., April 1, 2003; 9(4): 1461 - 1468.
[Abstract] [Full Text] [PDF]

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 Pharmacol. Rev.Home page
R. Danesi, F. De Braud, S. Fogli, T. M. De Pas, A. Di Paolo, G. Curigliano, and M. Del Tacca
Pharmacogenetics of Anticancer Drug Sensitivity in Non-Small Cell Lung Cancer
Pharmacol. Rev., March 1, 2003; 55(1): 57 - 103.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
I. H. N. Wong, J. Zhang, P. B. S. Lai, W. Y. Lau, and Y. M. Dennis Lo
Quantitative Analysis of Tumor-derived Methylated p16INK4a Sequences in Plasma, Serum, and Blood Cells of Hepatocellular Carcinoma Patients
Clin. Cancer Res., March 1, 2003; 9(3): 1047 - 1052.
[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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 GutHome page
B M Ryan, F Lefort, R McManus, J Daly, P W N Keeling, D G Weir, and D Kelleher
A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up
Gut, January 1, 2003; 52(1): 101 - 108.
[Abstract] [Full Text] [PDF]

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 J. Clin. Pathol.Home page
C Jeronimo, R Henrique, P F Campos, J Oliveira, O L Caballero, C Lopes, and D Sidransky
Endothelin B receptor gene hypermethylation in prostate adenocarcinoma
J. Clin. Pathol., January 1, 2003; 56(1): 52 - 55.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
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.
Quantitative O6-Methylguanine DNA Methyltransferase Methylation Analysis in Curatively Resected Non-Small Cell Lung Cancer: Associations with Clinical Outcome
Clin. Cancer Res., January 1, 2003; 9(1): 223 - 227.
[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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 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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 JNCI J Natl Cancer InstHome page
H.-W. Chang, S. M. Lee, S. N. Goodman, G. Singer, S. K. R. Cho, L. J. Sokoll, F. J. Montz, R. Roden, Z. Zhang, D. W. Chan, et al.
Assessment of Plasma DNA Levels, Allelic Imbalance, and CA 125 as Diagnostic Tests for Cancer
J Natl Cancer Inst, November 20, 2002; 94(22): 1697 - 1703.
[Abstract] [Full Text] [PDF]

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 Cancer Epidemiol. Biomarkers Prev.Home page
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]

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 Cancer Epidemiol. Biomarkers Prev.Home page
G.-S. Qian, S.-Y. Kuang, X. He, J. D. Groopman, and P. E. Jackson
Sensitivity of Electrospray Ionization Mass Spectrometry Detection of Codon 249 Mutations in the p53 Gene Compared with RFLP
Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1126 - 1129.
[Abstract] [Full Text] [PDF]


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