Human Molecular Genetics, 2001, Vol. 10, No. 5 513-518
© 2001 Oxford University Press
Evolution of instability at coding and non-coding repeat sequences in human MSI-H colorectal cancers
1INSERM U434, CEPH, 27 rue Juliette Dodu, 75010 Paris, France and 2Department of Surgery, University of Western Australia, Nedlands, WA 6907, Australia
Received 9 November 2000; Revised and Accepted 8 January 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A number of human genes containing coding mononucleotide repeat sequences are particularly prone to mutations in tumors with defects in mismatch repair (MMR) genes (MSI-H cancers). In a large series of MSI-H colorectal tumors, we looked for mutations in 25 coding repeats contained in eight genes already known to be mutated in these cancers or in 17 other genes with an expected role in carcinogenesis. Mutations were found in 19 of the 25 candidate genes. Using a maximum likelihood statistical method, they were separated into two different groups that differed significantly in their mutation frequencies, and were likely to represent mutations that do or do not provide selective pressures during MSI-H tumoral progression, respectively. Three new target genes were found (GRB-14, RHAMM, RAD50). Our results provide evidence that MSI-H tumoral progression involves the cumulative mutations of a large number of genes. For each MSI-H tumor we calculated indexes representing the number of mutations found in genes of these groups. We also evaluated a shortening index at both the Bat-25 and Bat-26 non-coding mononucleotide tracts that are known to be almost always unstable in MSI-H cancers. A significant correlation was observed between instability at both coding and non-coding repeats, suggesting that Bat-25 and Bat-26 could be used as simple phenotypical markers of the tumoral evolution. A preferential order of mutations was deduced. During this process, hMSH3 alterations, a target gene encoding for a MMR protein, was found to play an important role by increasing the instability phenomenon characterizing these cancers.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Cancers showing microsatellite instability (MSI-H) are characterized by inactivating alterations of mismatch repair (MMR) genes that lead to an incapacity to recognize and repair errors that occur during DNA replication (1–3). Due to their repetitive sequence, microsatellites are particularly prone to errors during replication and their frequent instability in MSI-H tumors is used to identify this phenotype. The consensus definition for the MSI-H phenotype is instability in at least two of five microsatellites (4), two of which are the non-coding mononucleotide repeats Bat-26 and Bat-25 (5,6). It is now generally accepted that the MSI-H phenotype is present in 10–15% of colorectal, gastric and endometrial cancers and much less frequently in other cancer types (4). MSI-H tumors have different clinicopathological features compared with tumors without this phenotype (7), termed MSS, and the repertoire of genetic events involved in tumoral progression of both phenotypes is thought to be different (8). Recently, several genes mutated within coding mononucleotide repeats were suggested to play a role in MSI-H tumorigenesis (9–14). However, because of the high background of genetic instability that characterizes these tumors, it is difficult to establish which of these alterations plays a role in carcinogenesis. Five criteria were recently proposed at the Bethesda consensus meeting in order to distinguish mutations occurring in target genes from those occuring in ByStander genes in MSI-H tumors (4). These were (i) a high mutational frequency; (ii) biallelic inactivation; (iii) a role for the candidate target gene in a growth suppressor pathway; (iv) the occurence of alterations within the same pathway in MSI-negative tumors; and (v) in vitro or in vivo functional suppressor studies. The third and fourth criteria are contested (15) because it cannot be assumed that all the important pathways are currently known, and also because involved pathways may be different between MSI-H and MSS tumors. Thus, in the absence of functional criteria, most studies reporting instability in putative target genes have relied on the frequency of mutation of coding repeats.
In this work we analyzed a number of candidate genes (n = 25) containing coding repeat sequences in a large series of MSI-H tumors. We showed that these genes were significantly separated in at least two groups characterized by high and low mutation frequencies, and likely to contain Real Target genes for instability and ByStander genes without any expected role in these cancers, respectively. We also showed that the expected number of genes implicated in MSI-H carcinogenesis should be high. We measured indexes representing the cumulative number of mutations present in coding and non-coding repeats and found that their values were significantly correlated. As a consequence, we used them as ‘molecular clocks’ of MSI-H tumoral progression, and found several lines of evidence suggesting that mutation of hMSH3, one of the target genes encoding for a MMR protein, plays a crucial role by increasing tumor instability.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Analysis of instability at coding repeat sequences in MSI-H tumors
A total of 25 coding repeats were analyzed for instability in a series of 57 MSI-H and 65 non-MSI primary colorectal tumors, as well as in 8 MSI-H and 16 non-MSI colorectal cancer cell lines. With very few exceptions, the MSI-negative primary tumors and cell lines did not show size alteration in any of the coding repeats (2/1564 and 1/390 mutational events, respectively). This compared with 175/1156 and 66/197 mutational events observed in MSI-H primary tumors (P < 0.0001) and cell lines (P < 0.0001), respectively. The majority of genes (19/25 and 22/25 in MSI-H primary tumors and cell lines, respectively) were found to be altered at mutation frequencies ranging from 2 to 92% in MSI-H primary tumors and from 13 to 100% in cell lines (Fig. 1). The number of mutational events was significantly higher in cell lines compared with primary tumors (P < 0.0001). Biallelic mutational events were observed for eight genes in the MSI-H cell lines (TGFß-RII, n = 6; TCF-4, n = 2; BAX, n = 2; hMSH3, n = 1; caspase-5, n = 1; GLcNAc, n = 2; HUMGPRKLG, n = 1; ANG2, n = 1). In some cases, these were in genes found to be rarely or not at all mutated in MSI-H primary tumors (GLcNAc, HUMGPRKLG, ANG2). These results indicate that cell lines cannot be used to assess the level of instability occurring within repeats in MSI-H tumors.
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For MSI-H primary tumor samples only, we used a maximum likelihood method in order to determine if the instability observed for these loci was more likely accounted for by the existence of a single type of locus (null hypothesis; H0), or by the presence of two types of loci differing in their instabilities (alternate hypothesis; H1). Because TGFß-RII was found to be altered at an exceptionally high incidence (92%), it was considered to represent a particular type of locus and was thus excluded from the statistical analysis. This approach allowed us to reject the H0 hypothesis in favour of the H1 hypothesis (P < 2.10–18), supporting the existence of at least two distinct groups of genes containing coding repeats which differed in their mutability in MSI-H tumors. Under the H1 hypothesis, the highest likelihood was observed for two groups containing N1 = 9 and N2 = 15 loci, respectively, with the following parameters: p1 = 0.246; p2 = 0.0373;
= 9/24. The first group is likely to represent target genes in which the inactivating mutations are selected for during MSI-H tumoral progression. These include, beside the TGFß-RII gene, most of the known target genes (BAX, IGFIIR, TCF-4, caspase-5, hMSH3, hMSH6) as well as three new members (GRB-14, RHAMM, RAD50) (16–18). The second group comprised 15 genes that are unlikely to play a role in MSI-H tumoral progression. When genes containing coding repeats were grouped according to increasing mutation frequencies, a bimodal distribution was observed (Fig. 2) corresponding to the two groups individualized by the maximum likelihood method.
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Instability observed at coding and non-coding repeats in MSI-H tumors
For each MSI-H tumor we calculated mutational indexes representing the number of mutations found in genes considered as Real Targets (n = 10, MIRT) or ByStanders (n = 15, MIBS) for instability according to the criteria defined above. In the same series of MSI-H tumors we also evaluated instability at both the Bat-25 and Bat-26 non-coding mononucleotide tracts. As already known (19,20), we found that the lengths of BAT-25 and BAT-26 deletions correlated well with each other (P < 0.001; r = 0.44. data not shown). We thus defined for each tumor a cumulative shortening index at non-coding repeats (SINC) by adding the number of deleted base pairs for these two repeats. No significant correlation was observed between SINC and MIBS values (data not shown). A strong tendency for a positive correlation was observed between SINC and MIRT. Following extension of our analysis to a total of 80 MSI-H tumor samples, this correlation became significant (P < 0.01; r = 0.22; Fig. 3).
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Use of MIRT, MIBS and SINC global instability indexes as phenotypical markers of MSI-H tumoral progression
Medium SINC, MIBS and MIRT values were calculated for tumors mutated on each of the 10 target genes (Fig. 4). This provided an estimate of global instability rates at both coding and non-coding repeats specific for each gene alteration. hMSH3 was the target gene associated with the highest SINC, MIBS and MIRT values compared with those of other target genes. hMSH3 was also the only target gene for which significant differences were observed for the three medium index values in mutated and non-mutated MSI-H samples (psinc/hMSH3 = 0.038; pmibs/hMSH3 = 6.1 x 10–5; pmirt/hMSH3 = 5.1 x 10–6; data not shown). Moreover, by comparing mutational frequencies of each target gene in two subgroups of MSI-H cancers defined by MIRT, MIBS or SINC values lower or higher than the respective averages of these three indexes, hMSH3 alteration was more specific for MSI-H tumors characterized by high values of these three indexes. Indeed, in the low-MIRT, low-MIBS and low-SINC tumor subclasses, mutational frequency for hMSH3 was only 0, 0 and 7%, respectively as compared with 42, 42 and 30% in the corresponding high-indexes tumor subclasses (Fig. 5). Positive associations for the presence of mutation between hMSH3 and BAX (P = 0.025), RAD50 (P = 0.017) or GRB-14 (P < 0.01) were also observed. It has to be noted that these results were not observed for hMSH6, another MMR gene containing a coding repeat sequence. TGFß-RII inactivation appeared to be the earliest mutational event since it was quasi-systematic. Moreover, the only few tumors without alteration of this gene were sytematically found to be associated with the lowest SINC, MIRT and MIBS values (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The microsatellite instability phenomenon in MSI-H tumors has been described as a complex mechanism that depends on different factors including the size and the nature of the repeat sequence, its localization and its putative role in gene expression. Here, we selected for study repeats that were all comparable in their structure (mononucleotide sequences), localization (coding repeats in genes potentially implicated in human carcinogenesis) and size (8–10 bp). By analyzing the frequency of mutation within 25 coding repeats possessing these characteristics in a large series of MSI-H primary tumors, we were able to statistically classify them into at least two distinct groups with a cut-off value for mutation frequency of ~12%. The first group is likely to represent target genes in which frameshift mutations play a role in MSI-H carcinogenesis. The second group comprises genes in which alterations are probably due to the elevated background of instability that characterizes these tumors and are likely to have no functional consequences for tumoral progression.
Seventeen of the 25 genes presented here have not previously been analyzed in MSI-H tumors. Three were considered to be new Real Target genes based upon their mutational frequencies: GRB-14, which encodes for a member of the GRB-7 family that interacts with the PDGF-regulated serine kinase (16); RAD50, encoding for a protein implicated in a conserved multiprotein complex involved in recombinational DNA repair (17); and RHAMM, encoding for the intracellular hyaluronan-mediated motility receptor interacting with microtubules and actin filaments (18). Together with the seven ‘classical’ genes analyzed in this study (TGFß-RII, BAX, IGFIIR, TCF-4, caspase-5, hMSH3, hMSH6) (9–14), this results in a total of 10 target genes for instability. Other recent reports suggest that RIZ (21,22), PTEN (23), MBD4 (24,25), CHKI (26), Fas, Apaf-1 and Bcl-10 (27) genes also contain coding repeats selectively mutated in MSI-H tumors. We and others have screened for mutations in only a small subset of genes containing coding repeats. Furthermore, the majority of human gene sequences are yet to be described. The number of genes that are potentially true target genes for instability in MSI-H cancers is therefore likely to increase to a much greater number than the one already described. Some of the primary MSI-H tumors analyzed in the present study are mutated in 8 of the 10 target coding repeats and probably have alterations in other, yet to be identified, genes that also contain coding repeats. Cancer is described as a multi-step phenomenon (28), but if the progression model is applied to MSI-H tumors, there are likely to be too many events if all target genes for instability are considered. We suggest that most of the mutations described in coding repeats in MSI-H tumors, even if the gene is considered as a target gene, are not necessary for tumoral progression when taken as a single event. Rather, they may represent a single component of a set of alterations, each one with a minor but real consequence, and whose accumulation results in uncontrolled cell growth. According to this hypothesis, the discovery of a new target gene for instability in MSI-H cancers should not be considered in isolation, but rather as an additional event that increases the number of altered target genes as defined here by the MIRT index.
SINC, MIRT and MIBS were defined as a measure of global instability rates at both coding (MIRT for Real Target and MIBS for ByStander genes) and non-coding repeats (SINC for both Bat-25 and Bat-26 mononucleotide tracts). It has been already proposed that Bat-25 and Bat-26 could be progressively shortened and used as markers of tumoral MSI-H progression (20). The finding here of a significant positive correlation between MIRT and SINC values demonstrates this fact for the first time and confirms that this phenomenon could be used as a simple molecular clock of MSI-H tumoral evolution.
Based on this observation, we used these indexes in order to propose a preferential order of mutation of the 10 target genes described in this work, which was deduced from the average MIRT, MIBS and SINC values for tumors containing mutations in these genes (Fig. 4): the highest SINC, MIBS and MIRT values were associated with the hMSH3 target gene alteration. This target gene was the only one for which significant differences were observed for the three medium SINC, MIBS and MIRT values when comparing mutated and non-mutated MSI-H samples. Its alteration appeared also to be the more specific one for tumors with high MIRT, MIBS and SINC values (Fig. 5). Using these indexes, the quasi-systematic TGFß-RII inactivation was found as the first target gene alteration observed in these cancers. These observations allow us to tentatively propose the following model for MSI-H tumor progression: after the inactivation of a MMR gene such as hMSH2 or hMLH1, genes containing coding repeat sequences become particularly prone to mutation in these cancers. The first and quasi-systematic target of this process should be TGFß-RII, and this mutational event should occur at the transition between adenoma and carcinoma as has already been shown (29). TGFß-RII inactivation can then be followed by alterations of a few other target genes in MSI-H tumors characterized by a low global level of instability at both the coding and non-coding repeats. In some cases, an additional mutational event could occur by frameshift mutations within the hMSH3 MMR gene coding repeat. This event, by modifying the MMR phenotype, could play an important role during MSI-H tumoral progression by increasing the global instability phenomenon at both the coding and non-coding levels. This would in turn provoke a number of other alterations in genes containing coding repeats that may or may not play a role in MSI-H carcinogenesis.
In this work, we defined stringent criteria for the discrimination of ByStander from Real Target genes for instability in MSI-H tumors. Our results support the idea that MSI-H carcinogenesis is a cumulative process involving mutation of a large number of genes. They allowed us to construct a model in which, following alteration of a first MMR gene, hMSH3 inactivation is often a second crucial event during MSI-H tumoral progression. They also suggest that the length of deletion of non-coding repeats could be used as a simple phenotypic marker of this process. These findings result from the use of global instability indexes. Compared to studies that focus on instability of only one gene, these indexes may provide better markers of the complex MSI-H phenotype and should be of interest for the investigation of other biological and clinical properties of MSI-H tumors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Cell lines and tumor samples
Twenty-four cell lines were obtained from Dr Sordat (Institut Suisse de Recherches Expérimentales sur le Cancer, Epalinges, Switzerland), Dr Zweibaum (Villejuif, France), or purchased from the American Type Culture Collection. A total of 145 primary colorectal tumors from patients undergoing surgery for this disease were analyzed. These included 80 MSI-H and 65 non-MSI tumors. DNA was extracted by proteinase K digestion and phenol–chloroform.
Assessment of MSI
The MSI status of the 24 colorectal cancer cell lines has been described previously (30). MSI-H tumors were defined as those with somatic deletions in the mononucleotide repeat BAT-26, located within intron 5 of hMSH2, and BAT-25, located within intron 16 of c-kit. These have been shown to establish MSI status with an accuracy >99.5% (5,6).
Selection of the candidate genes
A systematic screening of human DNA sequence databases (GenBank) allowed us to identify a number of genes containing coding mononucleotide tracts of 8 (n > 500), 9 (n > 130) or 10 bp (n > 40) in length. Amongst the 9 or 10 bp repeats, we then selected those with a full-length coding sequence as well as a putative role in cell cycle, signal transduction or other pathways potentially involved in human carcinogenesis. Since only cDNA sequences were available in most cases, we chose primer sets flanking the repeat and giving an expected DNA fragment size of ~100 bp after PCR of genomic DNA. In about one-third of cases, no PCR product was observed, presumably due to the presence of large introns between primers. A total of 25 genes were analyzed in this study, including seven genes already published as targets for instability (TGFß-RII, IGFIIR, TCF-4, caspase-5) (9,10,13,14) even if the coding repeat was only 8 bp long (BAX, hMSH3, hMSH6) (11,12).
PCR amplifications and mutation analysis
PCR was performed with primers specific for each selected candidate gene (sequences available on request). The PCR products were separated on a 7 M urea/32% formamide/7% polyacrylamide gel, transferred overnight onto Hybond N+ nylon membrane and hybridized with the 32P-labeled antisense primer in each case as a probe.
Statistical analysis
Using a maximum likelihood method, we tested the H1 alternative hypothesis for the presence of two types of loci that differed in their instabilities versus the H0 null hypothesis for the presence of a single type of locus. Ni is the number of tumors tested at locus i and ni the number of tumors that exhibited an instability at this locus. The probability of demonstrating an instability at a given locus is, under the H0 hypothesis, p0 and, under the H1 hypothesis, p1 and p2 depending on which type of site it belongs to. For the latter hypothesis, is the proportion of sites with the p1 instability with respect to the total number of sites tested.
The ratio of likelihood is given by:
where
and
This ratio follows a 
2-squared distribution with two degrees of freedom.
Determination of MIRT, MIBS and SINC global instability indexes
For each tumor sample, MIRT and MIBS values were calculated by adding the number of mutations in genes considered, according to the criteria defined above, as Real Targets (n = 10, MIRT) or ByStanders (n = 15, MIBS) for instability, respectively. Results are given in percentages.
SINC values were obtained on the same samples by adding the deletions in base pairs observed at both Bat-25 and Bat-26 non-coding mononucleotide tracks.
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ACKNOWLEDGEMENTS |
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A.D. was recipient of a ‘poste d’accueil’ from the Institut National pour la Santé et la Recherche Médicale (INSERM). This work was partly supported by the Association pour la Recherche sur le Cancer.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +33 1 53 72 51 09; Fax: +33 1 53 72 51 58; Email: richard.hamelin@cephb.fr
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J. Plaschke, S. Kruger, B. Jeske, F. Theissig, F. R. Kreuz, S. Pistorius, H. D. Saeger, I. Iaccarino, G. Marra, and H. K. Schackert Loss of MSH3 Protein Expression Is Frequent in MLH1-Deficient Colorectal Cancer and Is Associated with Disease Progression1 Cancer Res., February 1, 2004; 64(3): 864 - 870. [Abstract] [Full Text] [PDF]
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D. Fallik, F. Borrini, V. Boige, J. Viguier, S. Jacob, C. Miquel, J.-C. Sabourin, M. Ducreux, and F. Praz Microsatellite Instability Is a Predictive Factor of the Tumor Response to Irinotecan in Patients with Advanced Colorectal Cancer Cancer Res., September 15, 2003; 63(18): 5738 - 5744. [Abstract] [Full Text] [PDF]
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M. Olivero, T. Ruggiero, N. Coltella, A. Maffe', R. Calogero, E. Medico, and M. F. Di Renzo Amplification of repeat-containing transcribed sequences (ARTS): a transcriptome fingerprinting strategy to detect functionally relevant microsatellite mutations in cancer Nucleic Acids Res., April 1, 2003; 31(7): e33 - e33. [Abstract] [Full Text] [PDF]
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V. Vassileva, A. Millar, L. Briollais, W. Chapman, and B. Bapat Genes Involved in DNA Repair Are Mutational Targets in Endometrial Cancers with Microsatellite Instability Cancer Res., July 15, 2002; 62(14): 4095 - 4099. [Abstract] [Full Text] [PDF]
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Y. Mori, F. Sato, F. M. Selaru, A. Olaru, K. Perry, M. C. Kimos, G. Tamura, N. Matsubara, S. Wang, Y. Xu, et al. Instabilotyping Reveals Unique Mutational Spectra in Microsatellite-Unstable Gastric Cancers Cancer Res., July 1, 2002; 62(13): 3641 - 3645. [Abstract] [Full Text] [PDF]
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A. Duval and R. Hamelin Mutations at Coding Repeat Sequences in Mismatch Repair-deficient Human Cancers: Toward a New Concept of Target Genes for Instability Cancer Res., May 1, 2002; 62(9): 2447 - 2454. [Abstract] [Full Text] [PDF]
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K. Suzuki, T. Dai, I. Suzuki, Y. Dai, K. Yamashita, and M. Perucho Low Mutation Incidence in Polymorphic Noncoding Short Mononucleotide Repeats in Gastrointestinal Cancer of the Microsatellite Mutator Phenotype Pathway Cancer Res., April 1, 2002; 62(7): 1961 - 1965. [Abstract] [Full Text] [PDF]
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J. C. Boyer, N. A. Yamada, C. N. Roques, S. B. Hatch, K. Riess, and R. A. Farber Sequence dependent instability of mononucleotide microsatellites in cultured mismatch repair proficient and deficient mammalian cells Hum. Mol. Genet., March 1, 2002; 11(6): 707 - 713. [Abstract] [Full Text] [PDF]
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A. Duval, M. Reperant, A. Compoint, R. Seruca, G. N. Ranzani, B. Iacopetta, and R. Hamelin Target Gene Mutation Profile Differs between Gastrointestinal and Endometrial Tumors with Mismatch Repair Deficiency Cancer Res., March 1, 2002; 62(6): 1609 - 1612. [Abstract] [Full Text] [PDF]
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S. Baranovskaya, J. L. Soto, M. Perucho, and S. R. Malkhosyan Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype PNAS, December 18, 2001; 98(26): 15107 - 15112. [Abstract] [Full Text] [PDF]
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