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[Cancer Research 60, 2368-2371, May 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Inactivation of the DNA Repair Gene O6-Methylguanine-DNA Methyltransferase by Promoter Hypermethylation Is Associated with G to A Mutations in K-ras in Colorectal Tumorigenesis1

Manel Esteller, Minoru Toyota, Montserrat Sanchez-Cespedes, Gabriel Capella, Miguel Angel Peinado, D. Neil Watkins, Jean-Pierre J. Issa, David Sidransky, Stephen B. Baylin and James G. Herman2

Tumor Biology, The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [M. E., M. T., D. N. W., J-P. J. I., S. B. B., J. G. H.]; Laboratori d’Investigacio Gastrointestinal, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025 Spain [G. C.]; Institut de Recerca Oncologica, Hospital Duran i Reynals, Barcelona, 08907 Spain [M. A. P.]; and Head and Neck Cancer Research, Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21206 [M. S-C., D. S.]

O6-Methylguanine DNA methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from the O6 position of guanine. O6-Methylguanine mispairs with thymine during replication, and if the adduct is not removed, this results in conversion from a guanine-cytosine pair to an adenine-thymine pair. In vitro assays show that MGMT expression avoids G to A mutations and MGMT transgenic mice are protected against G to A transitions at ras genes. We have recently demonstrated that the MGMT gene is silenced by promoter methylation in many human tumors, including colorectal carcinomas. To study the relevance of defective MGMT function by aberrant methylation in relation to the presence of K-ras mutations, we studied 244 colorectal tumor samples for MGMT promoter hypermethylation and K-ras mutational status. Our results show a clear association between the inactivation of MGMT by promoter hypermethylation and the appearance of G to A mutations at K-ras: 71% (36 of 51) of the tumors displaying this particular type of mutation had abnormal MGMT methylation, whereas only 32% (12 of 37) of those with other K-ras mutations not involving G to A transitions and 35% (55 of 156) of the tumors without K-ras mutations demonstrated MGMT methylation (P = 0.002). In addition, MGMT loss associated with hypermethylation was observed in the small adenomas, including those that do not yet contain K-ras mutations. Hypermethylation of other genes such as p16INK4a and p14ARF was not associated with either MGMT hypermethylation or K-ras mutation. Our data suggest that epigenetic silencing of MGMT by promoter hypermethylation may lead to a particular genetic change in human cancer, specifically G to A transitions in the K-ras oncogene.




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The Association of Death-associated Protein Kinase Hypermethylation with Early Recurrence in Superficial Bladder Cancers
Cancer Res., July 15, 2002; 62(14): 4048 - 4053.
[Abstract] [Full Text] [PDF]

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 JCOHome page
S. L. Gerson
Clinical Relevance of MGMT in the Treatment of Cancer
J. Clin. Oncol., May 1, 2002; 20(9): 2388 - 2399.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
K. W. Choy, C. P. Pang, K. F. To, C. B. O. Yu, J. S. K. Ng, and D. S. C. Lam
Impaired Expression and Promotor Hypermethylation of O6-Methylguanine-DNA Methyltransferase in Retinoblastoma Tissues
Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1344 - 1349.
[Abstract] [Full Text] [PDF]

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 Toxicol SciHome page
R. E. Watson and J. I. Goodman
Epigenetics and DNA Methylation Come of Age in Toxicology
Toxicol. Sci., May 1, 2002; 67(1): 11 - 16.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
A. O.-O. Chan, R. R. Broaddus, P. S. Houlihan, J.-P. J. Issa, S. R. Hamilton, and A. Rashid
CpG Island Methylation in Aberrant Crypt Foci of the Colorectum
Am. J. Pathol., May 1, 2002; 160(5): 1823 - 1830.
[Abstract] [Full Text] [PDF]

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 JNCI J Natl Cancer InstHome page
M. Esteller, G. Gaidano, S. N. Goodman, V. Zagonel, D. Capello, B. Botto, D. Rossi, A. Gloghini, U. Vitolo, A. Carbone, et al.
Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase and Survival of Patients With Diffuse Large B-Cell Lymphoma
J Natl Cancer Inst, January 2, 2002; 94(1): 26 - 32.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
J. Kwong, K.-W. Lo, K.-F. To, P. M. L. Teo, P. J. Johnson, and D. P. Huang
Promoter Hypermethylation of Multiple Genes in Nasopharyngeal Carcinoma
Clin. Cancer Res., January 1, 2002; 8(1): 131 - 137.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
P. Wolf, Y. C. Hu, K. Doffek, D. Sidransky, and S. A. Ahrendt
O6-Methylguanine-DNA Methyltransferase Promoter Hypermethylation Shifts the p53 Mutational Spectrum in Non-Small Cell Lung Cancer
Cancer Res., November 1, 2001; 61(22): 8113 - 8117.
[Abstract] [Full Text] [PDF]

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 CarcinogenesisHome page
M. Nakamura, T. Watanabe, Y. Yonekawa, P. Kleihues, and H. Ohgaki
Promoter methylation of the DNA repair gene MGMT in astrocytomas is frequently associated with G:C {->} A:T mutations of the TP53 tumor suppressor gene
Carcinogenesis, October 1, 2001; 22(10): 1715 - 1719.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
A. Rashid, L. Shen, J. S. Morris, J.-P. J. Issa, and S. R. Hamilton
CpG Island Methylation in Colorectal Adenomas
Am. J. Pathol., September 1, 2001; 159(3): 1129 - 1135.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
M. Esteller, R.-A. Risques, M. Toyota, G. Capella, V. Moreno, M. A. Peinado, S. B. Baylin, and J. G. Herman
Promoter Hypermethylation of the DNA Repair Gene O6-Methylguanine-DNA Methyltransferase Is Associated with the Presence of G:C to A:T Transition Mutations in p53 in Human Colorectal Tumorigenesis
Cancer Res., June 1, 2001; 61(12): 4689 - 4692.
[Abstract] [Full Text] [PDF]

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 Hum Mol GenetHome page
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]

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 Cancer Res.Home page
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]

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 Clin. Cancer Res.Home page
A. K. Virmani, C. Muller, A. Rathi, S. Zoechbauer-Mueller, M. Mathis, and A. F. Gazdar
Aberrant Methylation during Cervical Carcinogenesis
Clin. Cancer Res., March 1, 2001; 7(3): 584 - 589.
[Abstract] [Full Text]

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 Cancer Res.Home page
V. L. J. Whitehall, M. D. Walsh, J. Young, B. A. Leggett, and J. R. Jass
Methylation of O-6-Methylguanine DNA Methyltransferase Characterizes a Subset of Colorectal Cancer with Low-level DNA Microsatellite Instability
Cancer Res., February 1, 2001; 61(3): 827 - 830.
[Abstract] [Full Text]

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 NEJMHome page
M. Esteller, J. Garcia-Foncillas, E. Andion, S. N. Goodman, O. F. Hidalgo, V. Vanaclocha, S. B. Baylin, and J. G. Herman
Inactivation of the DNA-Repair Gene MGMT and the Clinical Response of Gliomas to Alkylating Agents
N. Engl. J. Med., November 9, 2000; 343(19): 1350 - 1354.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
M. Esteller, A. Sparks, M. Toyota, M. Sanchez-Cespedes, G. Capella, M. A. Peinado, S. Gonzalez, G. Tarafa, D. Sidransky, S. J. Meltzer, et al.
Analysis of Adenomatous Polyposis Coli Promoter Hypermethylation in Human Cancer
Cancer Res., August 1, 2000; 60(16): 4366 - 4371.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
R. Lu, W.-C. Au, W.-S. Yeow, N. Hageman, and P. M. Pitha
Regulation of the Promoter Activity of Interferon Regulatory Factor-7 Gene. ACTIVATION BY INTERFERON AND SILENCING BY HYPERMETHYLATION
J. Biol. Chem., October 6, 2000; 275(41): 31805 - 31812.
[Abstract] [Full Text] [PDF]


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