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Inactivation of the DNA Repair Gene O⁶-Methylguanine-DNA Methyltransferase by Promoter Hypermethylation is a Common Event in Primary Human Neoplasia¹

Tumor Biology, The Johns Hopkins Oncology Center [M. E., S. B. B., J. G. H.], Division of GI-Liver Pathology [S. R. H.], and Department of Pathology [P. C. B.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

	ABSTRACT

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The DNA repair protein O⁶-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the O⁶ position of guanine. MGMT expression is decreased in some tumor tissues, and lack of activity has been observed in some cell lines. Loss of expression is rarely due to deletion, mutation, or rearrangement of the MGMT gene, but methylation of discrete regions of the CpG island of MGMT has been associated with the silencing of the gene in cell lines. We used methylation-specific PCR to study the promoter methylation of the MGMT gene. All normal tissues and expressing cancer cell lines were unmethylated, whereas nonexpressing cancer cell lines were methylated. Among the more than 500 primary human tumors examined, MGMT hypermethylation was present in a subset of specific types of cancer. In gliomas and colorectal carcinomas, aberrant methylation was detected in 40% of the tumors, whereas in non-small cell lung carcinomas, lymphomas, and head and neck carcinomas, this alteration was found in 25% of the tumors. MGMT methylation was found rarely or not at all in other tumor types. We also analyzed MGMT expression by immunohistochemistry in relation to the methylation status in 31 primary tumors. The presence of aberrant hypermethylation was associated with loss of MGMT protein, in contrast to retention of protein in the majority of tumors without aberrant hypermethylation. Our results suggest that epigenetic inactivation of MGMT plays an important role in primary human neoplasia.

	Introduction

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MGMT³ is a DNA repair protein that removes mutagenic and cytotoxic adducts from O⁶-guanine in DNA (1) . Alkylation of DNA at the O⁶ position of guanine is an important step in the formation of mutations in cancer, primarily due to the tendency of the O⁶-methylguanine to pair with thymine during replication, resulting in a conversion of guanine-cytosine to adenine-thymine pairs in DNA (2) . Furthermore, the O⁶-alkylguanine-DNA adduct may cross-link with the opposite cytosine residues, blocking DNA replication (3) . MGMT protect cells against these lesions, transferring the alkyl group from the O⁶-guanine in DNA to an active cysteine within its own sequence in a reaction that inactivates one MGMT molecule for each lesion repaired (1) . Thus, the ability of a cell to withstand such damage is directly related to the number of MGMT molecules it contains and to the rate of de novo synthesis of MGMT.

The amounts of MGMT protein differ according to cellular type (4 , 5) and are decreased in some tumors, with respect to their normal tissue counterpart (5 , 6) . A subset of tumor cell lines, termed Mer-, lack MGMT activity (7) . Because loss of expression is not commonly due to deletion, mutation or rearrangement of the MGMT gene (7, 8, 9) , or mRNA instability (10) , other causes for loss of activity may be involved. Hypermethylation of normally unmethylated CpG islands in the promoter regions of many genes correlates with loss of transcription (11) , and the human MGMT gene possesses a CpG island (12) . Recent work has reported that methylation of discrete regions of the MGMT CpG island is associated with the silencing of the gene in cell lines (13, 14, 15) . To study the relevance of the promoter hypermethylation of the MGMT gene in vivo, we have examined a series of more than 500 primary human tumors and corresponding normal tissues for MGMT aberrant methylation using MSP. Our results indicate that, in certain human cancers, MGMT function is lost frequently in association with hypermethylation of the promoter region and that this event may be an important step in human tumorigenesis.

	Materials and Methods

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MSP.
DNA methylation patterns in the CpG island of the MGMT gene were determined by chemical modification of unmethylated, but not the methylated, cytosines to uracil and subsequent PCR using primers specific for either methylated or the modified unmethylated DNA (16) . Primer sequences of MGMT were for the unmethylated reaction 5'-TTTGTGTTTTGATGTTTGTAGGTTTTTGT-3' (upper primer) and 5'-AACTCCACACTCTTCCAAAAACAAAACA-3' (lower primer) and for the methylated reaction 5'-TTTCGACGTTCGTAGGTTTTCGC-3' (upper primer) and 5'-GCACTCTTCCGAAAACGAAACG-3' (lower primer). The annealing temperature was 59°C. Placental DNA treated in vitro with Sss I methyltransferase (New England Biolabs) was used as positive control for methylated alleles of MGMT, and DNA from normal lymphocytes was used as negative control for methylated alleles of MGMT.

Briefly, 1 µg of DNA was denatured by NaOH and modified by sodium bisulfite. DNA samples were then purified using Wizard DNA purification resin (Promega), again treated with NaOH, precipitated with ethanol, and resuspended in water. Controls without DNA were performed for each set of PCRs. Each PCR reaction (10 µl) was directly loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and visualized under UV illumination.

Immunohistochemical Staining for MGMT.
Sections of formalin-fixed, paraffin-embedded tissue (6 µm thick) were deparaffinized with xylenes for 30 min and dehydrated by using graded ethanols. Immunoperoxidase staining using diaminobenzidine as chromogen was performed with the TechMate 1000 automatic staining system (Ventana, BioTek Solutions, Tucson, AZ). Commercially available Mouse anti-MGMT monoclonal antibody (catalogue N99200; Novus Molecular Inc., San Diego, CA), previously referred to as mT3.1 (17) , at 1:100 dilution was used. This antibody has previously been demonstrated to be useful for immunohistochemistry and to correlate with O⁶-alkylguanine-DNA alkyltransferase activity (18) . Nuclear staining was determined by two authors (S. R. H. and P. C. B.) who did not have knowledge of the molecular analysis of those samples.

	Results

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MGMT Promoter Hypermethylation.
DNA obtained from 524 primary human tumors, cancer cell lines, and normal tissues was subjected to MGMT promoter methylation study using MSP. The region chosen for MGMT spans the area of greatest CpG density immediately 5' to the transcription start site, in an area previously found to be hypermethylated in Mer- cell lines (14 , 15) . To determine the specificity of our approach, the colon carcinoma cell lines SW48 and HT29, reported previously as a Mer-deficient (Mer-) line and proficient (Mer+) line (19) , respectively, were first studied. The SW48 cell line, which did not express MGMT, was fully methylated in this region, whereas the MGMT-expressing cell line HT29 was completely unmethylated (Fig. 1B) . The MGMT promoter methylation status was investigated further in a set of normal human tissues, including brain, colonic mucosa, breast, pancreas, lung, and peripheral blood lymphocytes. Among these normal tissues tested, all were completely unmethylated at the MGMT gene (Fig. 1A) . Thus, the methylation of MGMT identified in cell lines must have originated during tumor progression or in cell culture.

View larger version (50K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. MSP of MGMT. PBR32/Msp digest are shown at left as molecular weight markers. The presence of a visible PCR product in Lane U indicates the presence of unmethylated genes of MGMT; the presence of product in Lane M indicates the presence of methylated genes. A, normal tissues. Corresponding Lanes are: normal brain, colonic mucosa, lung, lymphocytes, liver, kidney, and breast; in vitro methylated DNA (IVD) as positive control for methylation; and water control for PCR. B, MSP of MGMT in cancer cell lines. Corresponding Lanes are: colon carcinoma cell lines HT-29 (Mer+), SW48 (Mer-), and LoVo (Mer+); in vitro methylated DNA as positive control for methylation; and water control for PCR. C, MSP of MGMT in primary gliomas. Corresponding Lanes are: primary gliomas (1–5), normal brain (NBrain), SW48 colon cancer cell line as positive control for methylation, normal lymphocytes as negative control for methylation, and water control for PCR reaction. D, MSP of MGMT in primary colorectal carcinomas. Corresponding Lanes are: primary colorectal carcinomas (1–6), SW48 as positive control for methylation, normal lymphocytes as negative control for methylation, and water control for PCR reaction. E, MSP of MGMT in primary lung carcinomas. Corresponding Lanes are: primary lung carcinomas (1–6), SW48 as positive control for methylation, normal lymphocytes as negative control for methylation, and water control for PCR reaction. F, MSP of MGMT in primary lymphomas. Corresponding Lanes are primary lymphomas (1–6).

Hypermethylation of the MGMT promoter was not a universal finding in cancers in general, however. In contrast to the tumor types described above, other tumor types had infrequent MGMT promoter methylation: 2 of 18 (11%) pancreatic carcinomas, 2 of 18 (11%) melanomas, 1 of 12 (8%) renal carcinomas, 2 of 31 (6%) acute leukemias (1 AML and 1 ALL), and 2 of 44 (4%) bladder carcinomas. Finally, no carcinomas of the breast (n = 36), endometrium (n = 17), ovary (n = 23), or SCLCs (n = 7) analyzed had aberrant MGMT methylation.

In primary tumors, unlike cancer cell lines that were often either completely methylated or completely unmethylated in this region of the MGMT CpG island (Fig. 1B) , hypermethylation of MGMT was always accompanied by amplification in the unmethylated reaction as well. The presence of this unmethylated MGMT region could indicate the presence of normal tissues in these nonmicrodissected samples, with unmethylated MGMT alleles, as observed in Fig. 1A . However, heterogeneity in the patterns of methylation in the tumor itself might also be present. To address this issue, we sought to determine the consequences of hypermethylation of the CpG island of MGMT on expression of this enzyme.

Expression of MGMT in Primary Tumors.
Levels of MGMT expression often vary in primary tumors (5 , 6) . MGMT activity in primary tumors may be affected by contamination of tumor tissue with normal cells, such as endothelial cells, reactive astrocytes, or infiltrating lymphocytes, which express MGMT. Previous studies comparing MGMT activity, Western blot analysis, and immunohistochemistry have demonstrated only a moderate association between these methods of determining MGMT expression in colon carcinoma and normal colon (20) . For these reasons, we analyzed MGMT expression by immunohistochemistry so that the expression in the neoplastic cells could be directly measured, using a previously characterized antibody (18) . We first examined cell lines with known MGMT expression and methylation patterns to validate this approach. Expression of MGMT was absent in SW48 (Mer- and hypermethylated at the MGMT promoter), but was present in the Mer+ colon cancer cell lines HT29 and LoVo (data not shown).

Paraffin sections from 31 human primary tumors (including 8 brain tumors, 9 colon carcinomas, and 14 lymphomas) were then studied for MGMT expression. The immunohistochemical data related to MGMT promoter hypermethylation are shown in Table 2 , and examples of the results obtained are shown in Fig. 2 . All sections examined had nuclear staining of MGMT in normal cells adjacent to or within tumors, although in some cases this staining was weak. This provided an internal positive control. Among the 31 total tumors analyzed, 13 were judged to have loss of MGMT expression, whereas 18 tumors expressed MGMT. The level of expression observed in tumors varied greatly, and tumors that expressed MGMT often demonstrated higher expression than adjacent normal tissue. In the majority of these high MGMT expressing tumors, the expression was homogeneously increased. However, some cell to cell variation within in the neoplastic cells was observed. This finding is consistent with previous studies in these and other tissue types that tumor formation may be associated with increased levels of MGMT (20, 21, 22, 23) . However, a subset of tumors had diminished or absent MGMT expression, and in these tumors, protein was absent in the majority of tumor cells, with only occasional cells expressing detectable MGMT protein. The loss of staining was most uniform in the lymphomas, with greater cellular heterogeneity in the colon and brain tumors. Similar heterogeneity has been reported in colon (20) and lung (23) carcinomas demonstrating decreased expression of MGMT measured by immunohistochemistry.

View larger version (203K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Immunohistochemistry of MGMT gene product in primary human tumors. A, anaplastic astrocytoma unmethylated at MGMT showing expression of the protein in tumor cell nuclei. B, glioblastoma multiforme with MGMT promoter hypermethylation lacking expression in the majority of malignant cells. C, colonic carcinoma unmethylated at MGMT expressing the protein, whereas another colonic carcinoma in D with aberrant methylation at MGMT shows complete lack of expression in tumor nuclei, but expression in stromal cells. E, follicular lymphoma unmethylated at MGMT promoter showing expression of the protein. F, diffuse lymphoma hypermethylated at MGMT demonstrating loss of MGMT expression.

	Discussion

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In cell culture, a causal relationship between methylation of the MGMT CpG island and transcriptional silencing of the gene has been demonstrated (13, 14, 15) . Our data now demonstrate that MGMT promoter hypermethylation associated with loss of expression is frequent in primary human neoplasia as well. The tight correlation between MGMT CpG island methylation and loss of expression in these tumors provides an explanation for the loss of MGMT activity previously reported in a subset of many tumor types (5 , 6 , 20 , 21 , 23 , 24) . However, in tumor types where we did not detect MGMT hypermethylation, such as breast, ovarian carcinoma, or meningioma, decreased MGMT activity is infrequent (5 , 6 , 24) .

Because MGMT plays a major role in the repair of the O⁶-methylguanine DNA adducts, which are formed after exposure to methylating agents [including the monofunctional alkylating agents MNU or MNNG (N-methyl-N’-nitro-N-nitrosoguanidine)] and to clinical drugs such as dacarbazine, procarbazine, temozolomide, lomustine [CCNU, 1-(2-chloroethyl)-3-cyclohesyl-1-nitrosourea], nimustine [ACNU, 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3–2(2-chloroethyl)-3-nitrousourea], and carmustine [BCNU, 1,3-bis(2-chloroethyl)-1-nitrousourea], our results identify potentially critical events in carcinogenesis and may define a set of chemosensitive tumors. During DNA replication, O⁶-methylguanine can pair with thymine, resulting in conversion of guanine-cytosine to adenine-thymine pairs in DNA (2) . Such mutations are often present in tumors induced by alkylating agents (25) . To counteract these effects, MGMT protein can remove such adducts before mutations result. Thus, MGMT gene knockout mice have a higher susceptibility to MNU-induced tumorigenesis, specifically manifesting more frequent lung adenomas and thymic lymphomas when compared with wild-type mice (26) . Our findings that primary NSCLCs and lymphomas are tumor types with frequent methylation-associated inactivation of the MGMT gene suggest that this epigenetic alteration may confer an increased risk of alkylating agent-induced carcinogenesis in the systems of these organs.

The importance of MGMT in carcinogenesis is also evident in the MGMT transgenic mice, who possess protection against skin carcinogenesis, thymic lymphomas, and aberrant crypt foci of the colon induced by alkylating agents (27, 28, 29) . Interestingly, simple methylating agents, such as MNU, ACNU (a CNU derivative), and NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone], a nitrosamine present in tobacco and tobacco smoke, have been shown to induce ras mutations (30, 31, 32) . Tumor types with silencing of the MGMT by aberrant promoter hypermethylation in this study include those that have a frequent rate of K-ras mutations described in the literature, such as colon, lung, and head and neck carcinomas (30) . This suggests that one potential consequence of loss of MGMT expression could be an increase in susceptibility to K-ras mutation. The MGMT transgenic mouse, in fact, is not only protected against aberrant crypt foci formation, but also has a lower incidence of crypt foci with G to A mutations in K-ras (29) . However, other tumors associated with carcinogen exposure, such as bladder carcinoma, and other tumors with a high rate of K-ras mutations, such as pancreatic carcinoma, were not frequent targets of MGMT promoter hypermethylation, suggesting that inactivation of MGMT is not required for the acquisition of K-ras mutations.

From a clinical standpoint, MGMT promoter hypermethylation with subsequent loss of MGMT expression might play a role in modulating chemosensitivity to alkylating agents. CNUs and methylating agents, such as streptozotocin, are commonly used in the treatment of neoplastic diseases such as brain tumors, colon carcinoma, malignant melanoma, Hodgkin’s disease, lymphoma, myeloma, and skin cancer. Among the tumors studied in the present study, gliomas, colon carcinomas, and lymphomas had the highest frequency of MGMT promoter hypermethylation. These tumor types, in addition to NSCLC, have all been reported to have decreased MGMT expression and activity (5 , 6 , 20 , 21 , 23 , 24 , 33) in a subset of tumors. Thus, the decreased MGMT activity observed in a significant fraction of these tumors and the response of the former tumor types to CNUs may be due, in part, to the lack of O⁶-chloroethylguanine repair by inactivation at MGMT by aberrant promoter methylation. The tight correlation between loss of expression at the protein level and hypermethylation of the MGMT 5' CpG island we report in our study directly links these two processes in vivo and suggests an important role for aberrant promoter hypermethylation of MGMT in primary human cancer.

	ACKNOWLEDGMENTS

 
We acknowledge numerous colleagues who provided primary tumor samples and cell lines for this study, most notably Dr. Adrian Merlo. We also thank Dr. Anthony Pegg for helpful discussion.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by NIH Grants CA43318, CA64928, CA62924, and CA54396. M. E. is a recipient of a Spanish Ministerio de Educacion y Cultura Award. J. G. H. is a Valvano Foundation Scholar. S. B. B. and J. G. H. receive research funding and are entitled to sales royalties from ONCOR, which is developing products related to research described in this study. The terms of this arrangement have been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies.

² To whom requests for reprints should be addressed, at Tumor Biology, The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, MD 21231. Phone: (410) 955-8506; Fax: (410) 614-9884; E-mail: hermanji{at}welchlink.welch.jhu.edu

³ The abbreviations used are: MGMT, O⁶-methylguanine-DNA methyltransferase; CNU, chloroethylnitrosourea; Mer, methyl excision repair; MNU, N-methyl-N-nitrosourea; MSP, methylation-specific PCR; NSCLC, non-small cell lung carcinoma.

Received 9/ 3/98. Accepted 1/ 4/99.

	REFERENCES

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				J.-C. LAI, J.-Y. WU, Y.-W. CHENG, K.-T. YEH, T.-C. WU, C.-Y. CHEN, and H. LEE O6-Methylguanine-DNA Methyltransferase Hypermethylation Modulated by 17{beta}-Estradiol in Lung Cancer Cells Anticancer Res, July 1, 2009; 29(7): 2535 - 2540. [Abstract] [Full Text] [PDF]

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				B. He, L. You, K. Uematsu, K. Zang, Z. Xu, A. Y. Lee, J. F. Costello, F. McCormick, and D. M. Jablons SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer PNAS, November 25, 2003; 100(24): 14133 - 14138. [Abstract] [Full Text] [PDF]

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				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]

				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. CpG Island Methylation in Sporadic and Neurofibromatis Type 2-Associated Schwannomas Clin. Cancer Res., November 15, 2003; 9(15): 5601 - 5606. [Abstract] [Full Text] [PDF]

				T. Nagasaka, G. B. Sharp, K. Notohara, T. Kambara, H. Sasamoto, H. Isozaki, D. G. MacPhee, J. R. Jass, N. Tanaka, and N. Matsubara Hypermethylation of O6-Methylguanine-DNA Methyltransferase Promoter May Predict Nonrecurrence after Chemotherapy in Colorectal Cancer Cases Clin. Cancer Res., November 1, 2003; 9(14): 5306 - 5312. [Abstract] [Full Text] [PDF]

				J. Heighway, G.P. Margison, and M.F. Santibanez-Koref The alleles of the DNA repair gene O6-alkylguanine-DNA alkyltransferase are expressed at different levels in normal human lung tissue Carcinogenesis, October 1, 2003; 24(10): 1691 - 1694. [Abstract] [Full Text] [PDF]

				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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				M. van Engeland, M. P. Weijenberg, G. M. J. M. Roemen, M. Brink, A. P. de Bruine, R. A. Goldbohm, P. A. van den Brandt, S. B. Baylin, A. F. P. M. de Goeij, and J. G. Herman Effects of Dietary Folate and Alcohol Intake on Promoter Methylation in Sporadic Colorectal Cancer: The Netherlands Cohort Study on Diet and Cancer Cancer Res., June 15, 2003; 63(12): 3133 - 3137. [Abstract] [Full Text] [PDF]

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