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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

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.]

	ABSTRACT

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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 p16^INK4a and p14^ARF 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.

	Introduction

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Although ras mutation is the most common oncogenic alteration in human cancer (1 , 2) , the incidence of K-ras activation varies widely among carcinomas. K-ras mutation is rare in human primary breast carcinomas but occurs in approximately one-half of colorectal carcinomas. ras oncogenes are transforming after single-point mutations within their coding sequences. Mutations in naturally occurring ras oncogenes have been localized in codons 12, 13, 59, and 61. Alteration of codon 12, GGT, is the most common change. Substitution of the wild-type glycine 12 by any other amino acid results in oncogenic activation of this molecule (1 , 2) .

The mutational spectrum of critical genes in cancer is often not completely random. The tumor suppressor p53, the most commonly mutated gene in human cancer, commonly undergoes C to T changes from deamination of methylated cytosines (3) . However, in the case of K-ras, the absence of a CpG dinucleotide at codon 12 prevents this alteration on either strand. In contrast, K-ras mutations often result from G to A transitions. In animal models, chemical carcinogens can target ras oncogene sequences. Some modified bases are highly mutagenic because of their miscoding properties, as is the case for O⁶-methylguanine, an adduct produced by several carcinogens, including N-MNU.³ O⁶-methylguanine is read as adenine by DNA polymerases, thus leading to the frequent generation of G to A transitions in K-ras (4) . Avoidance of this mutagenic effect is directly related to the presence of a functional DNA repair protein, MGMT (5) . MGMT removes alkyl groups, as well as larger adducts involving chloroethylations, at the O⁶ position of guanine in a reaction that inactivates one MGMT molecule for each lesion repaired. In vitro assays also show that endogenous MGMT expression protects mammalian cell lines from spontaneous G:C to A:T transitions in the aprt gene (6) . Further insight into the role of MGMT as a keeper of genome integrity comes from animal models. Transgenic mice overexpressing MGMT are protected against O⁶-methylguanine-DNA adducts caused by MNU (7) and against G to A mutations in K-ras in aberrant colorectal crypt foci (8) and lung tumors (9) in mice. No studies connecting these events in human cancer have been reported.

Genetic defects in MGMT have not been found in cancer, but hypermethylation of the MGMT CpG island as the cause of MGMT transcriptional silencing in cell lines defective in O⁶-methylguanine repair has been recognized (10, 11, 12, 13) . Recently, we have reported that the MGMT gene is epigenetically inactivated by promoter hypermethylation in many primary tumor types with specific patterns (12) . Although this change is not present in breast carcinomas, in which K-ras mutations are extremely rare, it occurs in approximately 40% of cases of colorectal carcinomas associated with the loss of MGMT expression (12 , 14) and is also frequent in non-small cell lung carcinoma (12) . In the present study, we examined whether the epigenetic silencing of MGMT might be linked to the presence of K-ras mutations in human colorectal tumorigenesis. We determined the MGMT methylation status and the presence and type of K-ras mutations in codons 12 and 13 in a large collection of primary colorectal carcinomas and adenomas. Our data show that MGMT promoter hypermethylation is an early event in human colorectal tumorigenesis, independent of the aberrant methylation of other genes, and linked to the appearance of G to A mutations in the K-ras oncogene.

	Materials and Methods

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Tumor Samples.
Initially, 79 colorectal carcinomas and 65 colorectal adenomas were obtained from surgical resection specimens of surgical patients at the Johns Hopkins Hospital. Specimen collection procedures were approved by the Joint Committee on Clinical Investigation (Institutional Review Board) of the Johns Hopkins University School of Medicine. Subsequently, 120 additional colorectal carcinoma samples were obtained from surgical patients at the Hospital de Sant Pau in Barcelona between July 1991 and July 1993 under the supervision of Dr. Gabriel Capella. The study protocol was approved by the Ethics Committee. This last set of samples has been previously characterized for K-ras and p53 mutations (15) and p14^ARF promoter hypermethylation (16) . All of the samples were frozen in liquid nitrogen immediately after resection and stored at -70°C until processing. DNA was extracted by standard methods.

Methylation-specific PCR.
DNA methylation patterns in the CpG island of the MGMT gene were determined by chemical modification of the unmethylated, but not the methylated, cytosines to uracil, and subsequent PCR using primers specific for either the methylated or the modified unmethylated DNA (17) . Primer sequences of MGMT were for the unmethylated reaction 5'-TTT GTG TTT TGA TGT TTG TAG GTT TTT GT-3' (upper primer) and 5'-AAC TCC ACA CTC TTC CAA AAA CAA AAC A-3' (lower primer) and for the methylated reaction 5'-TTT CGA CGT TCG TAG GTT TTC GC-3' (upper primer) and 5'-GCA CTC TTC CGA AAA CGA AAC G-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 PCR. Ten µl of each PCR reaction was directly loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and visualized under UV illumination.

Reverse Transcription-PCR.
RT-PCR was performed as described previously (16) , using 3 µg of total cellular RNA to generate cDNA. One hundred ng of this cDNA were amplified by PCR with primers for exon 5'-GCC GGC TCT TCA CCA TCC CG-3' and exon 5'-GCT GCA GAC CAC TCT GTG GCA CG- 3' of MGMT, which amplify a 211-bp product spanning sequence 339–527 from GenBank accession number M29971. RT-PCR for GAPDH served as a positive control (16) . Ten µl of each PCR reaction was directly loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and visualized under UV illumination. The colorectal cancer cell lines HT-29 and RKO, unmethylated at the MGMT promoter (12 , 13) , and MGMT proficient were used. The colorectal cell line SW48, hypermethylated at the MGMT promoter that lacks MGMT expression, (12) was used as negative control.

Detection of K-ras Mutations.
Mutations at codons 12 and 13 of the K-ras gene were detected and characterized by an artificial RFLP/PCR approach (18) and mutant allele-specific amplification (19) . Mutations were confirmed by direct cycle sequencing of the PCR products using the AmpliCycle Sequencing kit (Perkin-Elmer, Branchburg, NJ).

	Results

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MGMT Promoter Hypermethylation and the Occurrence and Type of K-ras Mutations.
Among 244 colorectal lesions, 179 carcinomas, and 65 adenomas, 103 (42%) demonstrated hypermethylation of MGMT. Representative examples of the methylation analysis in colorectal carcinomas and adenomas are shown in Fig. 1A . Of these 244 samples, 88 (36%) had mutant K-ras. These two events were related because 48 (55%) of the 88 tumors with mutant K-ras had methylated MGMT, whereas only 55 (35%) of the 156 tumors without K-ras mutations had methylated MGMT (Fischer’s exact test, two-tailed, P = 0.003).

View larger version (56K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. A, examples of altered methylation status of the MGMT promoter in colorectal tumors and adenomas by methylation-specific PCR. 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 of MGMT. Top panel, pairs of normal colon (NC) and primary colorectal carcinomas (CRC) from three patients. Note the presence of a product for hypermethylated MGMT sequences in patients 1 and 3. Bottom panel, primary colorectal adenomas (A19, and so forth). Note hypermethylation of MGMT in samples A24 and A1. Normal lymphocytes and the colorectal carcinoma cell line SW48 were used as negative and positive control for MGMT methylation, respectively. B, graphical distribution of MGMT hypermethylation-associated inactivation in colorectal tumorigenesis as a function of K-ras mutational spectrum. C, expression of MGMT determined by RT-PCR in colorectal adenomas and control colon cancer cell lines. + and -, the addition or absence of reverse transcriptase in the generation of cDNA. Expression of MGMT was abundant in the cell lines HT29 and RKO, unmethylated at MGMT. In the colorectal cell line SW48 methylated at MGMT, the expression was abolished and only was present after treatment with the demethylating agent 5-aza-2'-deoxycytidine. Adenomas without methylation also demonstrated strong MGMT expression (A14, A19, A28, A25, A29) whereas those with MGMT methylation had absent (A1, A5, A7, A26) or markedly reduced (A4, A6, A11, A15) levels of MGMT expression. The latter may reflect either normal tissue contamination or low levels of MGMT expression in the adenomatous cells themselves. GAPDH expression (bottom panel) demonstrates the integrity of the cDNA.

Alternatively, an association between MGMT promoter hypermethylation and K-ras mutations could result from epigenetic inactivation of MGMT leading to K-ras mutation through the lack of O⁶-methylguanine repair. This relationship would be predicted to result in predominantly G to A transitions. Our data clearly support this latter mechanism: 71% (36 of 51) of tumors with G to A mutation in K-ras showed MGMT epigenetic inactivation, whereas only 32% (12 of 37) of the tumors with other K-ras mutations and 35% (55 of 156) of those without K-ras mutations exhibited aberrant methylation of the MGMT promoter. K-ras G to A transitions in codon 12 versus codon 13 had a similar distribution of MGMT aberrant methylation, 69% (29 of 42) versus 78% (7 of 9), respectively. Fig. 1B displays in a graphic way the distribution of MGMT promoter hypermethylation according to the K-ras status. The frequency of MGMT methylation in the G to A mutation group was statistically different from tumors with non-G to A K-ras mutations (Fischer’s exact test two-tailed, P < 0.0005) or tumors without K-ras mutations (Fischer’s exact test two-tailed, P < 0.0001). Thus, MGMT methylation is tightly linked only to the presence of G to A mutations in K-ras and not to other K-ras mutations.

Timing of MGMT Hypermethylation-associated Inactivation.
To further explore the role for MGMT deficiency in the genesis of G to A K-ras mutations, we examined the timing of both events. If the inactivation of MGMT leads to G to A mutations in K-ras, it would be expected that the loss of MGMT expression would precede K-ras alterations in colorectal tumorigenesis. Although MGMT promoter hypermethylation has been associated with a loss of MGMT function in primary colorectal carcinomas (12 , 14) and cancer cell lines (10, 11, 12, 13) , we confirmed this tight correlation examining the expression of MGMT using RT-PCR in colorectal adenomas. Ten colorectal adenomas without MGMT methylation expressed high levels of MGMT mRNA, whereas 19 polyps with MGMT methylation expressed very little (n = 5) or no detectable MGMT mRNA (n = 14; Fig. 1C ). Thus, just as in the invasive tumors, transcriptional loss was associated with MGMT hypermethylation (12 , 14) . To further demonstrate that the promoter methylation leads to loss of MGMT expression, the treatment of the colorectal cell line SW48—methylated at MGMT and without MGMT expression—with the demethylating agent 5-aza-2'-deoxycytidine restored MGMT expression (Fig. 1C) .

Within the colorectal lesions described above, we then investigated these changes in relation to stage of the disease. MGMT methylation was present in equal frequency in small adenomas <1 cm (9 of 21, 43%), large adenomas 1 cm (23 of 44, 52%), and carcinomas (71 of 179, 40%), which suggests that this change occurs early in neoplastic progression. However, in large adenomas and carcinomas, hypermethylation of MGMT was associated with G to A mutations in K-ras (9 of 12 large adenomas and 27 of 39 carcinomas with G to A mutations had MGMT methylation), whereas in small adenomas, no G to A mutations were observed, even in the 9 adenomas with MGMT methylation. Thus, MGMT promoter hypermethylation (and its consequence, MGMT transcriptional inactivation) is an early event in colorectal tumorigenesis, often appearing before the development of large adenomas, and this event precedes the appearance of K-ras mutations in colorectal tumors.

	Discussion

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A large amount of information concerning the genetic alterations found in human cancer has been compiled in recent years. However, we still know very little about the causes behind the DNA instability and enhanced mutational rates of a cancer cell. For the tumor suppressor p53, the deamination of CpG dinucleotides has been established as one of its important mutagenic events (8) . Other genes with potential relevant roles in cancer, such as BAX or TGFBRII, suffer very specific mutations in sporadic tumors with compromised mismatch repair (21, 22) . Silencing of the DNA repair gene hMLH1 by promoter hypermethylation is the probable event behind these defects in colorectal and endometrial cancer (23, 24, 25) . In this report, we provide another example of the interaction between epigenetic and genetic events in human cancer. Our data suggest that epigenetic silencing of the DNA repair gene MGMT by hypermethylation is strongly associated with, and precedes, G to A mutations in K-ras in colorectal tumorigenesis. This change would result from persistence of the promutagenic adducts in the O⁶ position of guanine that are not repaired by MGMT. Alkylating agents causing the promutagenic lesion may be provided from dietary nitrates reduced in the proximal colon by bacteria, by nitrosation of amines and amides derived of protein catabolism (26, 27, 28) . A previous study had suggested that loss of enzyme activity in the normal mucosa was found in patients with G to A mutations in K-ras but could not make this association in tumors (29) . However, in our study, the temporal relationship between inactivation of MGMT and the appearance of K-ras mutation in tumors with MGMT inactivation suggests a strong link between these two events.

It is of interest to take note of the tumor types for which MGMT promoter hypermethylation is a frequent event. It is known that in mouse models, the mammary tumors induced by MNU harbor characteristically G to A mutations in H-ras (30) . Strikingly, the absence of K-ras mutations is a common feature of sporadic human breast carcinomas. Concordant with these phenomena, MGMT is not inactivated by promoter hypermethylation in breast tumors (12) . On the other hand, for example, colorectal and non-small cell lung carcinomas have both changes: K-ras mutations (1 , 2) and MGMT promoter hypermethylation (12) . An interesting case arises from the brain tumors. Among the glial tumors, MGMT epigenetic inactivation (12) and MGMT loss or reduced activity (31 , 32) are common features, but ras mutations are infrequent. These data may reflect a different spectrum of carcinogen exposure, i.e., O⁶-ethylguanine is removed faster than the O⁶-methylguanine that prevents ras mutations (33) , or a different target gene more important for the biology of brain tumors than K-ras mutations. Thus, whereas the present study comments solely on G to A transitions in the K-ras gene, one important aspect of our data concerns the fact that each guanine in the human genome may generate a promutagenic lesion in the absence of correct repair. Other genetic alterations and mutations in target genes in human cancer that might be induced by MGMT epigenetic inactivation should receive close attention, and a search for these changes should be the focus of future investigations.

	ACKNOWLEDGMENTS

 
We thank Bert Vogelstein for the review of the manuscript.

	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 M. E. is a recipient of a Spanish Ministerio de Educacion y Cultura Award.

² To whom requests for reprints should be addressed, at Tumor Biology, The Johns Hopkins Oncology Center, 1650 Orleans Street, Baltimore, MD 21231. Phone: (410) 955-8506. Fax: (410) 614-9884. E-mail: hermanji{at}jhmi.edu

³ The abbreviations used are: MNU, methylnitrosourea; MGMT, O⁶-methylguanine DNA methyltransferase; RT-PCR, reverse transcription-PCR; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.

Received 12/10/99. Accepted 3/15/00.

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