Gene Promoter Hypermethylation in Tumors and Serum of Head and Neck Cancer Patients

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Gene Promoter Hypermethylation in Tumors and Serum of Head and Neck Cancer Patients¹

Montserrat Sanchez-Cespedes², Manel Esteller², Li Wu, Homaira Nawroz-Danish, George H. Yoo, Wayne M. Koch, Jin Jen, James G. Herman and David Sidransky³

Department of Otolaryngology–Head and Neck Surgery, Division of Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21206-2198 [M. S-C., L. W., W. K., J. J., D. S.]; The Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 [M. E., J. G. H.]; and Department of Otolaryngology-Head and Neck Surgery, Wayne State University, Detroit, Michigan 48201 [G. H. Y., H. N-D.]

Promoter hypermethylation is an important pathway for repressionof gene transcription in cancer cells. We analyzed aberrantDNA methylation at four genes in primary tumors from 95 headand neck cancer patients and then used the presence of thismethylation as a marker for cancer cell detection in serum DNA.These four genes were tested by methylation-specific PCR andincluded: p16 (CDKN2A), O⁶-methylguanine-DNA-methyltransferase,glutathione S-transferase P1, and death-associated protein kinase(DAP-kinase). Fifty-five % (52 of 95) of the primary tumorsdisplayed promoter hypermethylation in at least one of the genesstudied: 27% (26/95) at p16, 33% (31 of 95) at O⁶-methylguanine-DNA-methyltransferase;and 18% (17 of 92) at DAP-kinase. No promoter hypermethylationwas observed at the glutathione S-transferase P1 gene promoter.We detected a statistically significant correlation betweenthe presence of DAP-kinase gene promoter hypermethylation andlymph node involvement (P = 0.014) and advanced disease stage (P= 0.016). In 50 patients with paired serum available for epigeneticanalysis, the same methylation pattern was detected in the correspondingserum DNA of 21 (42%) cases. Among the patients with methylatedserum DNA, 5 developed distant metastasis compared with theoccurrence of metastasis in only 1 patient negative for serumpromoter hypermethylation (P = 0.056). Promoter hypermethylationof key genes in critical pathways is common in head and neckcancer and represents a promising serum marker for monitoringaffected patients.

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H.-Z. Zou, B.-M. Yu, Z.-W. Wang, J.-Y. Sun, H. Cang, F. Gao, D. H. Li, R. Zhao, G.-G. Feng, and J. Yi
Detection of Aberrant p16 Methylation in the Serum of Colorectal Cancer Patients
Clin. Cancer Res., January 1, 2002; 8(1): 188 - 191.
[Abstract] [Full Text] [PDF]

A. Forastiere, W. Koch, A. Trotti, and D. Sidransky
Head and Neck Cancer
N. Engl. J. Med., December 27, 2001; 345(26): 1890 - 1900.
[Full Text] [PDF]

G. Shohat, T. Spivak-Kroizman, O. Cohen, S. Bialik, G. Shani, H. Berrisi, M. Eisenstein, and A. Kimchi
The Pro-apoptotic Function of Death-associated Protein Kinase Is Controlled by a Unique Inhibitory Autophosphorylation-based Mechanism
J. Biol. Chem., December 7, 2001; 276(50): 47460 - 47467.
[Abstract] [Full Text] [PDF]

A. V. Velentza, A. M. Schumacher, C. Weiss, M. Egli, and D. M. Watterson
A Protein Kinase Associated with Apoptosis and Tumor Suppression. STRUCTURE, ACTIVITY, AND DISCOVERY OF PEPTIDE SUBSTRATES
J. Biol. Chem., October 12, 2001; 276(42): 38956 - 38965.
[Abstract] [Full Text] [PDF]

K. Hibi, M. Taguchi, H. Nakayama, T. Takase, Y. Kasai, K. Ito, S. Akiyama, and A. Nakao
Molecular Detection of p16 Promoter Methylation in the Serum of Patients with Esophageal Squamous Cell Carcinoma
Clin. Cancer Res., October 1, 2001; 7(10): 3135 - 3138.
[Abstract] [Full Text] [PDF]

P. Cairns, M. Esteller, J. G. Herman, M. Schoenberg, C. Jeronimo, M. Sanchez-Cespedes, N.-H. Chow, M. Grasso, L. Wu, W. B. Westra, et al.
Molecular Detection of Prostate Cancer in Urine by GSTP1 Hypermethylation
Clin. Cancer Res., September 1, 2001; 7(9): 2727 - 2730.
[Abstract] [Full Text] [PDF]

S. M. Dong, H.-S. Kim, S.-H. Rha, and D. Sidransky
Promoter Hypermethylation of Multiple Genes in Carcinoma of the Uterine Cervix
Clin. Cancer Res., July 1, 2001; 7(7): 1982 - 1986.
[Abstract] [Full Text] [PDF]

G. Sozzi, D. Conte, L. Mariani, S. Lo Vullo, L. Roz, C. Lombardo, M. A. Pierotti, and L. Tavecchio
Analysis of Circulating Tumor DNA in Plasma at Diagnosis and during Follow-Up of Lung Cancer Patients
Cancer Res., June 1, 2001; 61(12): 4675 - 4678.
[Abstract] [Full Text] [PDF]

S. B. Baylin, M. Esteller, M. R. Rountree, K. E. Bachman, K. Schuebel, and J. G. Herman
Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer
Hum. Mol. Genet., April 1, 2001; 10(7): 687 - 692.
[Abstract] [Full Text] [PDF]

M. Esteller, P. G. Corn, S. B. Baylin, and J. G. Herman
A Gene Hypermethylation Profile of Human Cancer
Cancer Res., April 1, 2001; 61(8): 3225 - 3229.
[Abstract] [Full Text]

M. F. Spafford, W. M. Koch, A. L. Reed, J. A. Califano, L. H. Xu, C. F. Eisenberger, L. Yip, P. L. Leong, L. Wu, S. X. Liu, et al.
Detection of Head and Neck Squamous Cell Carcinoma among Exfoliated Oral Mucosal Cells by Microsatellite Analysis
Clin. Cancer Res., March 1, 2001; 7(3): 607 - 612.
[Abstract] [Full Text]

W. M. Grady, A. Rajput, J. D. Lutterbaugh, and S. D. Markowitz
Detection of Aberrantly Methylated hMLH1 Promoter DNA in the Serum of Patients with Microsatellite Unstable Colon Cancer
Cancer Res., February 1, 2001; 61(3): 900 - 902.
[Abstract] [Full Text]

S. L. B. Rosas, W. Koch, M. d. G. d. C. Carvalho, L. Wu, J. Califano, W. Westra, J. Jen, and D. Sidransky
Promoter Hypermethylation Patterns of p16, O6-Methylguanine-DNA-methyltransferase, and Death-associated Protein Kinase in Tumors and Saliva of Head and Neck Cancer Patients
Cancer Res., February 1, 2001; 61(3): 939 - 942.
[Abstract] [Full Text]

S. Jahr, H. Hentze, S. Englisch, D. Hardt, F. O. Fackelmayer, R.-D. Hesch, and R. Knippers
DNA Fragments in the Blood Plasma of Cancer Patients: Quantitations and Evidence for Their Origin from Apoptotic and Necrotic Cells
Cancer Res., February 1, 2001; 61(4): 1659 - 1665.
[Abstract] [Full Text]

S. B. Baylin, S. A. Belinsky, and J. G. Herman
Aberrant Methylation of Gene Promoters in Cancer--Concepts, Misconcepts, and Promise
J Natl Cancer Inst, September 20, 2000; 92(18): 1460 - 1461.
[Full Text] [PDF]