[Cancer Research 62, 1609-1612, March 15, 2002]
© 2002 American Association for Cancer Research
Target Gene Mutation Profile Differs between Gastrointestinal and Endometrial Tumors with Mismatch Repair Deficiency1
Alex Duval,
Maryline Reperant,
Aurore Compoint,
Raquel Seruca,
Guglielmina N. Ranzani,
Barry Iacopetta and
Richard Hamelin2
INSERM U434-CEPH, 75010 Paris, France [A. D., M. R., A. C., R. H.]; Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200 Porto, Portugal [R. S.]; Department of Genetics and Microbiology, University of Pavia, 27100 Pavia, Italy [G. N. R.]; and Department of Surgery, University of Western Australia, Nedlands, 6907 Australia [B. I.]
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ABSTRACT
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Mutation frequencies at 25 genes containing coding repeats were comparedin colorectal, gastric, and endometrial mismatch repair-deficient (MSI-H) tumors. The overall number of mutations was significantly lower in endometrial than in gastrointestinal MSI-H cancers. Using a likelihood statistical method, target genes were divided in each tumor location into two groups likely to represent gene mutations that do or do not provide selective pressures during tumoral progression. Mutation profiles were quite similar in gastric and colorectal MSI-H cancers but were different in endometrial MSI-H tumors. Deletions in Bat-25 and Bat-26 noncoding repeats were also significantly less important in endometrial as compared with gastrointestinal MSI-H tumors. Our results show that the profile of target gene mutations in MSI-H tumors is tissue specific, with both qualitative and quantitative differences between gastrointestinal and endometrial MSI-H cancers.
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Introduction
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Cancers with MMR3
deficiency are characterized by global instability at the nucleotide level that affects, in particular, microsatellite repetitive sequences (MSI-H cancers; Refs. 1, 2, 3
). Because the simple inactivation of an MMR gene is not by itself a transforming event (4)
, additional genetic changes are believed necessary in order for MSI-H cells to become malignant. To date, the underlying genetic mechanism of carcinogenesis in MSI-H tumors is thought to involve mainly the mutation of repeat sequences contained within coding regions of genes having a putative role in human cancer.
MSI-H can occur within the context of the hereditary nonpolyposis colorectal cancer syndrome, as well as in 
10–15% of sporadic colorectal, gastric, and endometrial carcinomas (5)
. Among the target gene mutations reported in MSI-H tumors, most were first described in colorectal cancers. The majority was also shown to occur with variable frequency in gastric and/or endometrial MSI-H tumors. Although some differences have been reported depending on the primary site of the cancers, little is known of the influence that the tissue of tumor origin could have on the prevalence of target gene mutations in MSI-H tumors. By examining 25 candidate genes in MSI-H tumors derived from three different primary sites, the aim of this study was to better characterize possible tissue-specific influences.
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Materials and Methods
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Tumor Samples and Assessment of MSI.
MSI-H primary tumors from the colon (n = 48), stomach (n = 49), and endometrium (n = 42) were analyzed in this study. These tumors were selected from a larger series, and their MSI status 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, as described previously (6
, 7) .
Selection of Candidate Target Genes.
A group of 25 genes containing a mononucleotide repeat sequence in their coding region was analyzed for mutations. Most had been investigated previously for mutations in a large series of MSI-H colorectal tumors (8)
. They had earlier been reported as candidate targets for instability in MSI-H cancers or were identified by systematic screening of human DNA sequence databases (GenBank) as genes potentially involved in human carcinogenesis. All contain coding mononucleotide tracts from 8 to 10 bp in length.
Mutation Analysis.
PCR of the DNA surrounding each repeat sequence 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. Mutations were determined by the presence of additional bands to the normal alleles and were generally not sequenced. Sequencing of the RHAMM PCR product that had shown multiple additional bands previously revealed, however, that some of these were nonspecific, leading to overestimation of the mutation frequency in colorectal MSI-H cancers (8)
.
Statistical Analysis.
A maximum likelihood method was developed that considers MSI-H colorectal, gastric, and endometrial tumors independently (8)
. The H1 hypothesis (alternative hypothesis for the presence of two types of loci that differ in their level of instability) and the H0 hypothesis (null hypothesis for the presence of a single type of locus with respect to instability) were tested for each primary tumor site. Ni was the number of tumors tested at locus i, and ni was the number of tumors that exhibited mutation of this locus in each case. The probability of demonstrating instability at a given locus was, under the H0 hypothesis, p0 and, under the H1 hypothesis, p1 or p2 depending on the type of locus to which it belongs. For the latter hypothesis, 
was the proportion of sites with 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 distribution with two degrees of freedom.
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Results
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Instability in Coding Region Mononucleotide Tracts Varies with the Primary Site of MSI-H Tumor Origin.
A total of 25 genes containing coding repeats of 8–10 bp in size were analyzed for mutations in sporadic MSI-H cancers from the stomach (n = 49) or endometrium (n = 42). The results were compared with those already reported in a subset (n = 48) of a larger series of sporadic MSI-H colorectal cancers (8)
. All 25 repeats were shown previously to be monomorphic in a large series of non-MSI tumor DNA samples (8)
. The frequencies of mutation observed for each coding mononucleotide tract are shown in Fig. 1
for each type of MSI-H cancer. The majority of candidate target genes was found to be mutated at variable frequencies in each tumor type. The cumulative total of mutations observed in endometrial MSI-H cancers (60 of 881, 6.8%) was significantly lower than that observed in colon (151 of 1009, 15%) or gastric (147 of 979, 15%) MSI-H tumors (P = 0.0001 for each, Student’s t test). Gastric and colorectal MSI-H cancers were characterized by comparable mutation frequencies of these coding repeats (P = 0.98, Student’s t test).
Instability in Noncoding Region Mononucleotide Tracts Varies with the Primary Site of MSI-H Tumor Origin.
Similar results were obtained when the level of instability in the Bat-25 and Bat-26 noncoding repeats was evaluated by estimating the length of allelic deletions in these two repeats (Fig. 2)
. The lengths of Bat-25 and Bat-26 deletions were significantly less important in endometrial compared with colon (Bat-25, P = 1.1 10-10; Bat-26, P = 1.5 10-10) or gastric (Bat-25, P = 9.3 10-7; Bat-26, P = 1.8 10-10) MSI-H tumors (Student’s t test). Gastric and colorectal MSI-H tumors showed comparable lengths of deletions for these two noncoding loci. For each primary tumor site, the lengths of Bat-25 and Bat-26 deletions correlated well with each other, as reported earlier for MMR-deficient sporadic colorectal cancers (data not shown). The previously defined SINC index (Ref. 8
; total number of deleted bp for the Bat-25 and Bat-26 repeats) was calculated for each tumor sample. For each MSI-H tumor type, positive correlations were observed between the total number of target gene mutations and SINC values (data not shown).
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Fig. 2. Comparative analysis of the average length of deletion in the Bat-25 and Bat-26 mononucleotide repeats, or the sum of deletions in both repeats, in colorectal, gastric, and endometrial MSI-H primary tumors.
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Target Gene Mutations Show Tissue Specificity in MSI-H Tumors.
The frequency of mutation of the 25 target genes included in this study was evaluated using a likelihood statistical method (8)
described previously. Each tumor series was considered independently. For each primary tumor site, mutations within coding repeats were more likely to be accounted for by the existence of at least two types of loci that differ in their level of instability (alternate hypothesis; H1) rather than by the presence of only one type of locus (null hypothesis; H0). Because TGFßRII mutations were observed at very high frequencies in colorectal (92%) and gastric (81%) but not endometrial (19%) MSI-H tumors, as already reported (9)
, this locus was included for statistical analysis only in the latter tumor type. In gastrointestinal MSI-H tumors, TGFßRII was considered to be a distinct type of locus and was, thus, excluded from the analysis. Cutoff values that define loci with different mutation propensity for mutation were revealed by the likelihood method to be 10–15% for colorectal, 17–21% for gastric, and 6–8% for endometrial MSI-H tumors. When genes containing coding repeats were plotted according to increasing frequency of mutation, a bimodal distribution was observed for all three primary tumor sites (Fig. 3)
. The partition boundaries were comparable with the cutoff values defined by the likelihood method. In each case, one of the groups is likely to represent real target genes for instability whereby frameshift mutations are selected for during MSI-H tumoral progression. The other group probably represents bystander genes for mutation, and these are unlikely to play a role in the progression of MSI-H cancers. For colorectal and gastric MSI-H tumors, the two groups contained almost the same genes. The major exception was mutation of the T-cell transcription factor-4 gene, which was 3-fold more frequent in colorectal compared with gastric MSI-H cancers. The TGFßRII, Bax, IGFIIR, hMSH3, hMSH6, and GRB-14 genes all appeared to be real targets for instability in both gastrointestinal and endometrial MSI-H cancers, whereas mutation of the RAD-50 gene as a real target gene appears limited to the former. Conversely, mutations in the DNA-dependent protein kinase catalystic subunit, Glnac, CCAAT-box binding factor, and CtBP-interacting protein coding regions appeared to be specific for endometrial but not gastrointestinal MSI-H tumors.
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Fig. 3. Genes containing coding repeats are grouped according to increasing frequency of mutation in colorectal (black), gastric (dark gray), or endometrial (white) MSI-H primary tumors. A bimodal distribution is observed for each primary tumor site, similar to the two groups of genes predicted by the likelihood statistical method.
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Discussion
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The present work is a comparative analysis of the MSI phenomenon in MSI-H cancers derived from three different primary sites. The results support some of our recent proposals concerning MSI-H colorectal carcinogenesis (8)
. Similar to this tumor type, it was demonstrated in MSI-H gastric and endometrial cancers that genes containing coding repeats could also be separated into at least two groups characterized by high and low mutation frequencies. A similar bimodal distribution can be deduced from recent published data on MSI-H colorectal cancers (10)
. These two groups are likely to represent real target genes for instability and bystander genes, respectively. However, such a classification should not be considered watertight. A bystander gene could have a relatively high mutation rate because of the length of the repeat and to the nature of adjacent sequences. Alternatively, a real target gene for instability might be involved in only a subset of tumors depending on the presence of other genetic alterations. Notwithstanding these possibilities, the mutation frequency is still likely to be a useful indicator of the functional role played by a specific gene; mutations in real target genes should provide selective pressures during tumorigenesis but not those occurring in bystander genes. Thus, irrespective of the site of primary tissue origin, MSI-H carcinogenesis appears to be a complex process involving cumulative mutations to many genes, only a fraction of which are likely to have functional consequences.
The major finding of this work is that selection of target gene mutations in MSI-H cancers is a tissue-specific process. Whereas some of the genes analyzed here were proposed to be real target genes for mutation in all three types of MSI-H tumors (TGFßRII, BAX, IGFIIR, MSH3, MSH6, and GRB14; Refs. 8
and 11, 12, 13, 14
), the selection of other genes for mutation appeared to be dependent on the primary localization of the tumor. MSI-H endometrial carcinomas accumulate significantly fewer mutations at coding repeats compared with gastrointestinal MSI-H tumors, e.g., the almost systematic TGFßRII gene mutation in MSI-H gastrointestinal tumors was observed in only 
20% of the MSI-H endometrial cancer cases in this series. This was despite the prediction from the likelihood method that it would be selected for during endometrial tumorigenesis. Hence, we propose that most of the real target genes that play a role in MSI-H endometrial tumor progression are altered at a relatively low frequency in this cancer type.
More generally, our results confirmed that gastrointestinal MSI-H cancers were characterized by a similar group of gene mutations, whereas target genes involved in MSI-H endometrial carcinogenesis were more specific for this tumor type. Thus, different pathways are likely to be involved in the progression of MMR-deficient tumors depending on their site of primary origin. These results were obtained using the same method and at the same institute, regardless of the tumor origin or of the gene being analyzed. They are in general agreement with published data in the literature on target genes for instability in MSI-H tumors.4
As proposed earlier for MSI-H colorectal cancers (8)
, the length of deletion of noncoding repeats, such as Bat-25 and Bat-26, could also be used as a simple molecular marker for the cumulative mutation process in gastric and endometrial MSI-H cancers. This observation may be explained by the progressive shortening of long, noncoding mononucleotide repeats during tumor evolution (3
, 15, 16, 17, 18)
.
The use of a large target gene approach on MSI-H tumors derived from three different primary sites has revealed quantitative and qualitative differences in the mutation profile of these cancers and extends previous observations on smaller number of target genes (19
, 20)
. Biallelic inactivation of the hMLH1 gene by de novo methylation of its promoter was shown to be the main inactivating mechanism of the MMR system in sporadic colorectal (21
, 22)
, gastric (23
, 24)
, and endometrial (25)
MSI-H cancers. Therefore, it is unlikely that the differences in target gene mutations observed here between gastrointestinal and endometrial MSI-H cancers are because of different MMR defects. They may instead be related to a number of complex and as yet unidentified, tissue-specific biological characteristics. More powerful approaches, such as those analyzing the whole transcriptome and/or the proteome, could be used to provide a more detailed characterization of the MSI-H phenotype in cancers originating at different primary sites.
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FOOTNOTES
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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 grants from the Association pour la Recherche contre le Cancer and by a grant from the INSERM/CNR Memorandum of Understanding for missions. A. D. was a recipient of a poste d’accueil from Institut National pour la Santé et la Recherche Médicale (INSERM). 
2 To whom requests for reprints should be addressed, at INSERM U434-CEPH, 27 rue Juliette Dodu, 75010 Paris, France. Phone: 33 1 53 72 51 09; Fax: 33 1 53 72 51 58; E-mail: richard.hamelin{at}cephb.fr
3 The abbreviations used are: MMR, mismatch repair; MSI, microsatellite instability; TGF, transforming growth factor.
4 A. Duval and R. Hamelin, Mutations at coding repeat sequences in mismatch repair deficient human cancers: towards a new concept of target genes for instability, submitted for publication.
Received 10/11/01.
Accepted 1/29/02.
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ABSTRACT
Introduction
