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Alterations of the DNA Repair Gene OGG1 in Human Clear Cell Carcinomas of the Kidney¹

Commissariat à l’Energie Atomique, Département de Radiobiologie et Radiopathologie [M. A., S. C., C. L., S. B., J. P. R.] and UMR217 Centre National de la Recherche Scientifique/Commissariat à l’Energie Atomique [M. A., S. B., J. P. R.], BP6, F92265 Fontenay aux Roses, France; Centre National de Séquençage, F94000 Evry, France [G. G.]; Département d’Anatomie et de Cytologie Pathologiques, Hôpital Cochin, F75014 Paris, France [A. V.]; Cytopathologie et Cytométrie Cliniques LRC/CEA #14, Institut Curie, F75248 Paris, France [J. K., P. V., A. K. E. N.]; and Service d’Oncologie Médicale, Hôtel Dieu, F95004 Paris, France [S. O.]

	ABSTRACT

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The OGG1 gene, which codes for a DNA repair protein with antimutator activity, is located on chromosome 3p25, a frequent site of allelic deletions in many types of human tumors, including renal clear cell cancers. We present the analysis of 99 renal tumors for alterations in the OGG1 gene to determine its association with tumorigenesis. Loss of heterozygosity in the 3p25 region was found for 85% of the informative cases. We detected somatic missense mutations of the OGG1 gene in 4 of the 99 tumor samples. Biochemical analysis of the mutant proteins revealed that a substitution at codon 46 impairs the enzymatic activity. We also describe the occurrence of several polymorphisms as well as aberrantly spliced OGG1 transcripts.

	Introduction

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Damage to DNA by oxygen free radicals is postulated to cause mutations associated with the initiation and/or progression of human cancers (1 , 2) . Oxidative damage-induced mutations can activate oncogenes or inactivate TSGs,³ altering the cell growth control (3) . An oxidatively damaged guanine, 8-OxoG,is abundantly produced in DNA as a consequence of cellular oxidative metabolism or exposure to ionizing radiation or chemical carcinogens (4 , 5) . The presence of 8-OxoG in DNA has been shown to be mutagenic because, although this lesion does not impede DNA chain elongation, it preferentially pairs to adenine during in vitro DNA synthesis (6) . Studies using bacterial or yeast mutants defective in the elimination of 8-OxoG have demonstrated that the accumulation of this base generates a mutator phenotype characterized by a high frequency of G:C to T:A transversions (reviewed in Ref. 7 ). In mammalian cells, the OGG1 gene codes for an 8-OxoG DNA glycosylase/AP lyase that has the capacity to excise this oxidized guanine from DNA. The Ogg1 protein initiates the base excision repair process by recognizing and excising the modified base. Consistent with the yeast findings, mice lacking a functional Ogg1 protein accumulate abnormal levels of 8-OxoG in their genomes and display a moderately elevated spontaneous mutation rate in nonproliferative tissues (8) . Because inactivation of the OGG1 gene in mammalian cells causes a mutator phenotype, it can be expected that cells lacking Ogg1 activity could have an enhanced probability of undergoing cancer transformation (9) . The validation of this hypothesis requires the identification of human tumors where both alleles of the OGG1 gene are nonfunctional. Analysis of the sequence changes in the p53 suppressor gene showed a bias in favor of GC to TA transversions in lung and kidney cancers (10) . This type of mutation would be expected in cells incapable of eliminating 8-OxoG from their DNA and therefore likely to be deficient in the OGG1 gene. Furthermore, the human OGG1 gene has been located on chromosome 3p25 (11) . Human chromosome 3p cytogenetic abnormalities and LOH have been observed at high frequency in sporadic forms of RCC. Three loci on chromosome 3p have been shown to be frequently involved in RCCs: (a) 3p14.1–3p14.3; (b) 3p21.2–3p21.3; and (c) 3p25; however, the relative contribution of each locus is not well known. The FHIT gene locus at 3p14.2 covers about 500 kb, including the fragile site FRA3B and the constitutional t(3;8) breakpoint associated with the development of multiple RCCs. Because only a few sporadic nonpapillary RCCs have a deletion breakpoint within the FRA3B/FHIT region and because most renal cell tumors show a normal FHIT transcript, the involvement of the FHIT gene and the FRA3B region can be excluded from the genetics of RCC (12) . The 3p21.2-p21.3 locus is frequently deleted in RCC and also in other cancers, but to date, no candidate gene has been identified. The VHL TSG at 3p25–26 is strongly implicated in the pathogenesis of clear cell RCC. It has been established that (a) VHL methylation is a specific and important event in the pathogenesis of RCC; (b) in RCC with 3p LOH but without VHL inactivation, mutations in TSGs at 3p14-p21 appear to have a primary role in tumorigenesis; and (c) inactivation of other 3p TSGs in addition to VHL may also be required for malignant transformation in tumors with VHL gene inactivation (13) .

Here we analyze a series of 99 clear cell kidney tumors and matched normal tissues for mutations in OGG1 and for LOH in the region of chromosome 3p harboring this gene. The variant alleles of the Ogg1 protein were expressed in Escherichia coli and analyzed for their enzymatic activities.

	Materials and Methods

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Tissue Samples.
This study was conducted on a series of 99 clear cell RCCs and the corresponding normal tissue surrounding each of them obtained after surgery and kept in liquid nitrogen until used. The mean size of the tumors was 6.8 cm (range, 2–23 cm). Twenty-eight percent of patients had stage I tumors, 40% of patients had stage II tumors, 21% of patients had stage III tumors, and 11% of patients had stage IV tumors. RNA and DNA preparations were done using RNAplus and DNAzol extraction kits (Quantum Appligen, Illkirch, and Life Technology, Cergy-Pontoise, France).

LOH Analysis.
Mapping of the OGG1 gene was performed by amplification from a hybrid radiation panel as described previously (14) , using the following OGG1 cDNA-specific oligonucleotides: (a) 5'-GCTGTTCAGTGCCGACCT; and (b) 5'-AACATGAGACTGGGTGGGG. For LOH analysis, 0.2 µg of DNA from each sample was subjected to PCR using primers directed against the following chromosome 3p highly polymorphic microsatellite markers: (a) AFM238wb12; (b) AFM295yc9; and (c) AFM095xc1. The primer sequences and PCR conditions used were those obtained from the Genome Database.⁴ For each pair, one of the primers was labeled with Cy5, a fluorescent dye. PCR products were separated on 6% denaturing PAGE. Gels were run and analyzed on an ALFexpress automated sequencer (Amersham Pharmacia Biotech). Homozygosity was classified as noninformative. LOH was calculated by comparing the ratios between the peak areas of the two alleles in the tumor with that in the corresponding normal tissue. Differences larger than 30% were considered to be a LOH.

Mutation Analysis.
OGG1 mutations were screened by DGGE analysis of RT-PCR-amplified materials as described previously (15) . Samples with an altered DGGE profile were then sequenced. Study of the OGG1 cDNA melting domain profile showed that five independent RT-PCRs were mandatory to analyze nucleotides 309-1250. The 3'-end of the cDNA sequence was analyzed systematically by sequencing because alternative splicing occurs within this region. For DGGE analysis, a psoralen clamp was attached at the 5'-end of one of each of the primer pairs, whose sequences are given in Table 1 . Each RT-PCR was carried out in a final volume of 100 µl using one-fiftieth of cDNA template obtained from 1 µg of total RNA mixed with 50 pmol of each forward and reverse primer in 10x PCR buffer containing 27 mM MgCl₂. After denaturing for 2 min at 94°C, 32 cycles consisting of 50 s at 94°C, 50 s at the appropriate annealing temperatures (Table 1) , and 20 s at 72°C were performed using an automatic DNA thermal cycle (MJ Research). The last cycle was followed by an additional 10 min at 72°C to complete all of the products, and a 10-µl aliquot was electrophoresed on a 2% agarose gel in 1x Tris-borate EDTA and examined by ethidium bromide staining to confirm the presence of the appropriately sized product. Heteroduplex and homoduplex formations were performed by incubating each PCR product for 5 min at 94°C and 45 min at 55°C, and stabilization of the duplexes was obtained by UV irradiation at 365 nm for 20 min, which provokes a covalent link at the 5'-end of both strands of DNA due to the presence of the photoactivatable intercalating psoralen group. Denaturant PAGE of the stabilized duplexes (30 µl) was carried out at 60°C using a thermostated gel apparatus (Prolabo, Paris, France). Gels contained 7% acrylamide in 1x TEA buffer [40 mM Tris-acetate, 1 mM EDTA (pH 8.0)] with linearly increasing gradients of the denaturants urea and formamide (100% denaturant corresponds to 40% formamide and 7 M urea). The respective gradients and running conditions for each DGGE are given in Table 1 . PCR products of wild-type and known mutants, obtained using point mutated oligonucleotides, were systematically included as controls with each set of test samples. After electrophoresis, the gels were stained with ethidium bromide and photographed under UV illumination at 354 nm. Each sample showing an abnormal electrophoresis profile, as compared with the wild-type migration, was subjected to an independent RT-PCR amplification using the appropriate primers without the psoralen clamp and purified by centrifugation through centricon-100 columns (Amicon). Sequencing reactions were carried out on both strands using the sequencing kit (Perkin-Elmer) on an ABI prism (Perkin-Elmer). For analysis of exons 6 and 7, the genomic region was PCR amplified using the oligonucleotides 5'-GGGCTGGGATGGTAGAAAC and 5'-CTGCTTGATTTGGGGGTG. PCR reactions were carried out in 50 µl containing 0.2 µg of genomic DNA, 50 pmol of each primer, 1.7 mM MgCl₂, 0.1 mM each deoxynucleotide triphosphate, 0.25 unit of Taq DNA polymerase (Roche), and 1x PCR buffer containing 17 mM MgCl₂. The reaction mixture was denatured for 3 min at 94°C and incubated for 35 cycles of denaturing for 50 s at 94°C, annealing for 50 s at 59°C, and extension for 30 s at 72°C. The final extension was continued for 5 min at 72°C. The fragment obtained was purified and sequenced as described above.

The enzymatic activity of the purified proteins was assayed by monitoring their capacity to cleave a 34-mer duplex oligonucleotide harboring an 8-OxoG:C bp (16) . In each reaction (10 µl, final volume), 50 fmol of ³²P-labeled 8-OxoG:C duplex were incubated in 25 mM Tris-HCl (pH 7.6), 2 mM Na₂EDTA, and 50 mM NaCl with 14 ng of each of the hOgg1 proteins for 15 min at 37°C. Reactions were stopped by adding 6 µl of formamide dye and subjected to 7 M urea-20% PAGE. Gels were scanned and quantified using a PhosphorImager (Molecular Dynamics).

	Results

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Allelic Status of the Region Harboring the OGG1 Gene.
Using radiation hybrid mapping, highly polymorphic markers around OGG1 were identified. Three of these microsatellite markers were selected to analyze LOH in the tumor samples. AFM238wb12 is a telomeric marker located 0.57 cR from OGG1. AFM295yc9 and AFM095xc1 are centromeric from OGG1 at 0.18 and 0.63 cR, respectively (14) . The regions located between the markers comprise several known and unknown genes. Among them, VHL has been assigned to the interval between the latter two markers.

DNA from both tumor and normal kidney tissues was obtained from 104 patients, and the allelic balance for the three polymorphic markers mentioned above was analyzed. Of the 99 patients, patients 82, 77, and 73 were heterozygous in the normal tissue for markers AFM238wb12, AFM295yc9, and AFM095xc1, respectively. The flanking markers AFM238wb12 and AFM095xc1 showed LOH in 65 of 82 (79%) and 59 of 73 (81%) informative cases. LOH for the central marker, the marker closest to OGG1, was observed in 83% (64 of 77) of the informative cases. Among the noninformative samples for this central marker, 12 cases showed loss of the two flanking markers. Based on the above results, we estimate the LOH for the region harboring OGG1 to occur in 76 of 89 informative samples (85%). Considering the location of the markers used, these data imply a concomitant loss of one VHL allele in the tumor samples.

OGG1 Alterations.
Two complementary strategies were used to screen for mutations in the coding sequences of OGG1. In the first strategy, total RNA was extracted from the tissue samples (99 cases) and used as substrates for cDNA synthesis. The cDNAs were analyzed by PCR-DGGE. In the cases where an abnormal migration pattern was observed, an independent PCR was performed, and the product was sequenced. Because of the presence of alternatively spliced forms of OGG1 mRNA (reviewed in Ref. 17 ), multiple fragments were generated during the amplification of the sequences spanning exons 6 and 7, thus interfering with the interpretation of the results. To circumvent this problem, genomic DNA was isolated, and the region spanning exons 6 and 7 was amplified by PCR and analyzed for the presence of mutations by sequencing both strands of the amplification products. The combination of these approaches led to the identification of variant forms of Ogg1 cDNA other than the frequent polymorphism at amino acid 326. Indeed, 22 tumor samples displayed altered forms of OGG1 cDNA. However, in eight cases, a new RT-PCR failed to detect the alteration. One explanation resides in the possibility of mutations being present in a small fraction of the tumor tissue. Analysis of the OGG1 transcript in the normal tissue was performed in all cases. Five of the 14 confirmed sequence changes were also present in the normal tissue and corresponded to polymorphisms. Table 2 displays the polymorphisms of the OGG1 gene found in this series. For polymorphism at position 326, the allelic frequency of the Cys form is 25%, which is not statistically different from the frequencies reported in other pathologies or in a normal population (18, 19, 20) . There is no preferential loss of one of the alleles in the tumors. The amino acid changes at positions 85 and 308 had already been reported in lung and head and neck tumors, respectively (19 , 21) . Reconstitution of the mutant proteins and their expression in bacteria show that the changes coded by these polymorphic alleles do not significantly affect the enzymatic activity of the Ogg1 glycosylase (data not shown; Ref. 19 ). Two new polymorphisms at codons 220 and 323 were found in this series. Neither of them produces changes at the amino acid level.

Characterization of the Mutant OGG1 Proteins.
To assess the functional status of the proteins coded by the mutant forms of the OGG1 gene found in the tumor samples, site-directed mutagenesis was performed on a plasmid coding for a glutathione S-transferase-OGG1 fusion (16) . The proteins carrying each of the four different amino acid substitutions were subsequently expressed in E. coli and purified. Their 8-OxoG DNA glycosylase activity was tested by determining their capacity to cleave an oligonucleotide harboring a unique 8-OxoG residue. Fig. 1 shows the results of a representative experiment. Using this assay, the mutants in codons 12, 169, and 232 show no difference in their enzymatic activity when compared with the wild-type form. However, in the case of the R46Q mutant, the DNA glycosylase/AP lyase activity is drastically reduced. Its specific activity is 4-fold lower than that of the corresponding wild-type version, suggesting a strong impairment in its DNA repair capacity.

View larger version (57K): [in this window] [in a new window]   Fig. 1. Repair activity of the mutant OGG1 proteins found in kidney tumors. Cleavage of an oligonucleotide harboring a unique 8-OxoG residue. Fourteen ng of each of the hOGG1 proteins were incubated with the 34-mer substrate (S) to yield a 16-mer product (P) of the combined glycosylase/AP lyase activity. Lane 1, no protein; Lane 2, G12E mutant; Lane 3, R46Q mutant; Lane 4, R169Q mutant; Lane 5, S232T mutant; Lane 6, wild type.

	Discussion

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The substitution in codon 46 corresponds to an amino acid conserved in all of the eukaryotic Ogg1, from yeast to human. The amino acid change shows a marked effect by impairing the in vitro enzymatic activity of the mutant OGG1 protein when expressed in E. coli. For the tumor in which this mutation was detected, homozygosity prevented LOH analysis of the region harboring the OGG1 gene. On the DGGE analysis of the tumor cDNA, a wild-type band was detected, but it could be attributed to contamination with normal host cells, which presented only the wild-type form of OGG1. Interestingly, the same base substitution was reported in the small cell lung carcinoma cell line NCI-H526 (18) , suggesting that such a mutation could be associated with the carcinogenic process. Recent elucidation of the crystal structure of hOGG1 shows that residue 46 is located in ß-sheet B, not far from Gly-42, which makes direct contact with 8-OxoG (23) .

Mutations in codons 12 and 232 affect nonconserved amino acids. Consistent with this is the lack of effect on the in vitro 8-OxoG DNA glycosylase activity of the mutant proteins. Residue 232 maps to the surface of the protein, whereas the position for residue 12 has not been mapped (23) . However, this mutation potentially alters the proposed mitochondrial localization sequence. In that case, substitution at position 12 would affect the level of DNA repair activity in mitochondria. As for the amino acid at position 169, it is conserved in the mammalian OGG1 genes, but not in the yeast gene. The substitution of arginine for a glutamine found at this position in case R48 does not affect the in vitro enzymatic activity but could interfere with the interaction between OGG1 and other proteins involved in the repair mechanism. Alternatively, the amino acid changes described could have consequences on the stability of the proteins in the cell. A more detailed biochemical characterization of these mutant forms is necessary to evaluate their potential effect on the DNA repair capacity of the cells harboring them.

In this study, several polymorphisms were detected in the OGG1 gene. The amino acid substitution at codon 326 was found at the same frequency reported previously for other types of cancers and in normal individuals. No specific bias was found in the loss of either allele in the RCC cases studied. Two rare polymorphisms leading to amino acid changes at positions 85 and 308 were also detected. These polymorphisms had previously been reported for lung and head and neck cancers, respectively (19 , 21) . In the in vitro assay, the proteins coded by these variants are functional 8-OxoG DNA glycosylases.

In the analysis of the OGG1 mRNA from the tumor samples, several deletion or insertion modifications were detected. Their location, together with the lack of DNA sequence changes in the OGG1 gene, indicates that they are the result of aberrant splicing of the primary transcript. Four of the six cases involved deletions starting at the 5'-end of exon 5. In all cases, the protein encoded by those messengers is likely be inactive. Because several alternatively spliced forms of OGG1 have been reported in cell lines and normal tissues, it remains to be determined whether the alternative spliced forms described here are characteristic of the tumor tissue. Such a situation may imply a defect in the RNA processing machinery specific to the tumor cells.

The dissociation between the high frequency of LOH and the inactivation of the OGG1 gene suggests only a minor impact of alterations in the OGG1 gene on the genesis of renal tumors. Similar results were found for gastric, lung, and head and neck cancers (18 , 19 , 24 , 25) . However, several possibilities for its involvement in the carcinogenic process remain to be investigated. Because there is loss of one of the alleles in 85% of the RCC cases studied, a dosage effect on the 8-OxoG repair cannot be ruled out. This is underscored by recent studies showing that tumors having lost one OGG1 allele have twice as much 8-OxoG in their DNA (20) . This could lead to a weak mutator phenotype. Alternatively, gene silencing could be totally or partially turning off the remaining OGG1 allele through methylation of the promoter CpG island (26) . Finally, because of the finding that some of the mutations detected in the original DGGE screen could not be confirmed by a second RT-PCR, the possibility of ongoing mutations having an effect on the progression of the tumor should be considered.

In conclusion, our analysis of 99 cases of renal cancers has identified four somatic mutations in OGG1, along with several polymorphisms. It is important to note that similar studies for other types of cancer failed to identify any mutation in primary tumors. One of the mutations clearly impairs the enzymatic activity of the gene product, whereas the other mutations could have more subtle effects on the DNA repair mechanism, possibly leading to different levels of mutator phenotypes that could contribute to tumorigenesis.

	ACKNOWLEDGMENTS

 
We thank Andreia Dhénaut for providing the OGG1 genomic sequence data. We also thank Claudine Dhérin and Eliane Padoy for excellent technical assistance.

	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 by funding from the Commissariat à l’Energie Atomique, the Centre National de la Recherche Scientifique, Electricité de France, and the Association pour la Recherche sur le Cancer.

² To whom requests for reprints should be addressed, at Département de Radiobiologie et Radiopathologie, Commissariat à l’Energie Atomique, 60 avenue du Général Leclerc, F92265 Fontenay aux Roses, France. Phone: 33-1-46-54-88-57; Fax: 33-1-46-54-88-59; E-mail: jpradicella{at}cea.fr

³ The abbreviations used are: TSG, tumor suppressor gene, 8-OxoG, 7,8-dihydro-8-oxoguanine; LOH, loss of heterozygosity; RCC, renal cell carcinoma; RT-PCR, reverse transcription-PCR; AP, abasic site; DGGE, denaturing gradient gel electrophoresis.

⁴ gdb.infobiogen.fr.

Received 3/21/00. Accepted 7/19/00.

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