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Mutations at Coding Repeat Sequences in Mismatch Repair-deficient Human Cancers

Toward a New Concept of Target Genes for Instability¹

Institut National de la Santé et de la Recherche Médicale U434: CEPH, 75010 Paris, France

	ABSTRACT

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Because the discovery of a link between mismatch repair deficiency and sporadic or inherited human cancers characterized by microsatellite instability (MSI-H tumors), genes containing coding repeat sequences have been found to be mutated at these repeats in MSI-H tumors from different primary sites as reported in the present review. Accumulation of such alterations appears to be the main molecular mechanism by which MSI-H cells accumulate functional changes with putative oncogenic effects. These mutations occur in many genes at variable frequencies. They can affect genes with a putative role in human carcinogenesis involved in different or similar pathways and are thus thought to be inactivating or activating events selected for in these cancers in a recessive or dominant manner. However, because of the high level of instability characterizing these cancers, they are also likely to occur in genes without any expected role in MSI-H carcinogenesis. In light of these recent data, the concept of target genes for instability and their possible role in MSI-H cancers is reconsidered here.

	Introduction

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Cancer is now generally accepted to be the result of a complex biological process involving many genes that regulate activities, including cell growth and/or death, cell motility, extracellular matrix remodeling, genomic stability, and DNA repair. Inactivation or activation of these genes can result from underlying genetic instability phenomenon and from epigenetic silencing. Different types of genetic instabilities have been described thus far in human tumors, including numerous genetic changes at both the chromosomal and nucleotide levels. Gene alterations can be because of point nucleotide changes, loss or gain of chromosome arms, chromosomal translocations, or gene amplifications. A subset of cancers is characterized by an MMR³ deficiency because of inactivating alterations of MMR genes. As a consequence, these tumors exhibit a particular phenotype called MSI, characterized by a global instability phenomenon affecting microsatellite repetitive sequences (1, 2, 3) . In 1997, a National Cancer Institute Workshop meeting held in Bethesda proposed a panel of five markers for the uniform detection of MSI tumors (4) . Tumors with instability at two or more of these markers were defined as being MSI-H, whereas those with instability at one repeat or showing no instability were defined as MSI-L and MSS tumors, respectively. MSI-H cancers have distinct clinicopathological features from MSI-L and MSS tumors. They can occur in the context of the HNPCC syndrome (5, 6, 7, 8) or can occur sporadically in as many as 10–15% of colorectal, gastric, and endometrial carcinomas (4) . Because the simple inactivation of an MMR gene is not thought to be by itself a transforming event, additional genetic changes are believed to be necessary for cells to become malignant. To date, most of these have been found in genes containing coding repeat sequences that are particularly prone to alterations in MSI-H cancers.

In 1995, TGFßRII was reported as the first target gene for instability in human colorectal MSI-H tumors (9) . This gene was shown to be heterozygously or homozygously mutated at a poly(A)10 coding repeat (1 or 2 bp deletions) in 9 of 11 MSI-H colorectal cell lines (82%). The repeat sequence was located at the beginning of the coding sequence and, hence, any frameshift alterations were proposed to be inactivating mutations. This mutation was then confirmed by the same group to occur in a series of primary MSI-H colorectal cancers (10) . Moreover, functional studies demonstrated that these frequent frameshift alterations led to a loss of the TGFß-RII tumor suppressor function (11) . Later, four other genes containing coding repeats were shown to be altered at various frequencies in MSI-H cancers. These were the BAX, hMSH3, hMSH6, and IGFIIR genes, all showing the same type of alteration at (G)8, (A)8, (C)8, and (G)8 coding repeats, respectively (12, 13, 14) .

At this point in our knowledge of MSI-H carcinogenesis, the following criteria were proposed at the Bethesda consensus meeting to define target genes for instability in human cancers (4) : (a) high frequency of inactivation; (b) biallelic inactivation by simultaneous alteration of the second allele’s repeat tract or by point mutation or allelic loss; (c) involvement of the candidate MSI-H target gene in a bonafide growth suppressor pathway; (d) demonstration of inactivation of the same growth suppression pathway in MSS tumors through mutation of the same gene or of another gene within the same pathway; and (e) functional studies showing growth suppression in in vitro or animal models. These criteria have been questioned by others, however (15) : (a) it was noted that biallelic alteration of a coding repeat was not the only mechanism by which a putative tumor suppressor gene could be inactivated; imprinting of one allele, e.g., can eliminate the need for biallelic mutation; (b) the expected tumor suppressor function of a target gene was extended to include genes involved in cell senescence, cell differentiation, apoptosis, and the escape of immune surveillance; it was also proposed that some target genes could play a role in pathways specific to MSI-H cancers, without necessarily being involved in MSS tumors; and (c) some target genes have been shown not to be involved in a growth suppression pathway (e.g., MSH3 and MSH6). Because more than one target gene could be involved in the same signaling pathway, it was therefore proposed that reintroduction into a tumor cell of a wild-type target gene would not necessarily revert the transformed phenotype, as required by the criteria (15) .

Until now, these two studies constitute the only references that speculate on the definition of target genes for instability in human cancers. Here we review all studies in MSI-H tumors that report gene mutations at coding repeat sequences. On the basis of these published studies, we propose a reconsideration of the target gene concept.

Reported Target Genes for Mutations in MSI-H Cancers.
As discussed above, the TGFßRII, BAX, IGFIIR, MSH3, and MSH6 genes were the first described target genes for instability in MSI-H cancers (9 , 12, 13, 14) . A number of studies have now reported their mutation frequencies in colorectal MSI-H tumors, as well as in other MSI-H tumor types. More recently, a number of other genes with possible roles in human carcinogenesis and analogous mutations was described. These include ACTRII, AIM2, APAF-1, AXIN-2, BCL-10, BLM, Caspase-5, CDX-2, CHK-1, FAS, GRB-14, cell cycle protein hG4-1, KIAA0977, MBD-4, hMLH3, NADH ubiquinone oxidoreductase, OGT, PTEN, RAD-50, RHAMM, RIZ, SEC63, SLC23AT, TCF-4, and WISP-3 (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31) . Table 1 describes the size and nature of the repeats within each gene, the frequency of mutation reported by the major publications for sporadic colorectal, gastric, and endometrial MSI-H cancers, as well as for familial MSI-H tumors that were mainly colorectal carcinomas derived from HNPCC patients. We have intentionally excluded from this review E2F-4, the only gene known to be altered in a trinucleotide repeat. There is an absence of frameshift mutations in this gene, meaning the alterations have unclear functional significance compared with the distinct frameshift mutations observed in other target genes for instability.

Interpretation of MSI-H Carcinogenesis According to Different Primary Sites of the Tumors.
As shown in Table 1 , most studies report target gene alterations in sporadic MSI-H cancers derived from colon, stomach, or endometrium. Among the different target genes for MSI, only TGFßRII, BAX, IGFIIR, MSH3, and MSH6 have been analyzed extensively at all three of these primary tumor sites (Fig. 1) . The frequency of instability observed for these five target genes was quite comparable between MSI-H gastric and colorectal tumors. However, significant differences in the mutation frequencies between these two tumor types were observed for TGFßRII (f[colon] = 496 of 614; f[stomach] = 159 of 229; P = 4.10^-4) and MSH6 (f[colon] = 91 of 414; f[stomach] = 67 of 176; P < 0.0001). MSI-H endometrial tumors were characterized by a generally lower incidence of instability compared with gastrointestinal MSI-H tumors (Fig. 1) . Mutation frequencies for the TGFßRII, hMSH3, and hMSH6 genes were significantly lower in endometrial compared with gastrointestinal MSI-H tumors (P < 0.01 in each case). Inactivation of hMLH1 by methylation of its promoter is responsible for the large majority of MSI-H sporadic cancers, regardless of site of origin (76, 77, 78, 79, 80) . The differences in frequency of gene instability observed between endometrial and gastrointestinal tumors is therefore unlikely to be because of differences in the type of MMR gene alteration present in these cancers.

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Mutation frequencies reported for TGFßRII, Bax, IGFIIR, hMSH3, and hMSH6 coding repeat sequences in colorectal, gastric, and endometrial sporadic MSI-H cancers. The average mutation frequencies for each was calculated from results published in the literature.

Most studies performed on HNPCC tumors were carried out to confirm that target genes for instability were also mutated in these familial cancers. To date, most target genes have been found to be mutated at comparable frequencies between HNPCC and sporadic MSI-H tumors (Table 1) . However, the number of studies is still quite low, and most were performed on familial cases of colon cancer.

Different Functional Consequences for Different Target Gene Alterations.
We have indicated in Table 1 the functions of the genes described as target genes for instability. The expected outcome of frameshift alterations at coding repeat sequences may not always be a simple loss of function. Other mechanisms leading to a putative oncogenic effect were proposed recently. Alterations of such repeat sequences have been sometimes proposed to have a dominant negative effect. In the AXIN gene, e.g., the mutated protein was shown to be more stable compared with the wild type (23) . RIZ frameshift alterations occurring downstream of important domains of the protein may have other, unknown functional consequences (26) . In other cases, frameshift alterations are thought to be activating mutations, as proposed for the TCF-4 gene involved in the adenomatous polyposis coli/ß-catenin/TCF-4 pathway (81) . Here, the frameshift mutations within the (A)9 coding repeat are believed to enhance the transactivating properties of the protein by a complex mechanism that favors the synthesis of isoforms without the capacity to bind CtBP, a transcriptional repressor of the TCF/LEF family. Thus, similar to non-MSI tumor types, inactivating, as well as activating mutations, and recessive, as well as dominant mutations, might be expected to play a role in MSI-H carcinogenesis even if all can be generated from the same molecular mechanism. As a consequence, biallelic inactivation should not be considered as a strict criteria to define target genes in MSI-H tumors, in contrast to what has been proposed (4) . It should also be emphasized that heterozygous mutations leading to haploinsufficiency could sometimes be of functional significance in MSI-H tumors. These may be especially relevant in a number of cases where there is a synergistic effect with mutations in other target genes involved in the same pathway (22) .

Frequency of Target Gene Alterations and the High Level of Instability Characterizing MSI-H Tumors.
The number of genes described as containing coding repeat sequences that are mutated in MSI-H tumors has increased considerably (Table 1) . By developing a large candidate gene approach that includes 25 genes containing a coding repeat sequence, we showed the mutation frequency of such repeats was widely variable in a large series of MSI-H colorectal cancers (28) . Another recent publication reported that short, noncoding mononucleotide repeats localized within intronic gene sequences were also mutated, in some cases, with a surprisingly high frequency (50%) in these tumors (82) . In view of these findings, MSI-H cancers appear to represent a particular tumor type characterized by a high background for instability. The mutability of mononucleotide repetitions within these tumors may depend not only on functional but also on structural and possibly other, as yet unidentified factors. In this context, it could be argued that the criteria for defining a target gene in MSI-H tumors as a gene that is "frequently" altered in MSI-H cancers are not sufficiently precise.

Toward a New Concept for Target Gene Alterations in MSI-H Cancers.
The instability phenomenon is now widely recognized as one of the main mechanism by which genetic alterations accumulate in cancerous cells. In most human solid tumors, this phenomenon is most readily observed at the chromosomal level and leads to gene alterations by chromosomal gains or losses, chromosomal translocations, and gene amplifications. Because thousands of gene alterations are generated simultaneously and because all genes can in theory be the targets of such rearrangements, there clearly exist very powerful mechanisms for transforming cells. Chromosomal abnormalities are rare in MSI-H cancers, and these tumors are usually diploid with a normal karyotype. Therefore, MMR defects appear to be the major and specific molecular mechanism responsible for the generation of many mutations in noncoding and coding microsatellite sequences in MSI-H tumors.

Until now, MMR deficiency has been shown to be deleterious for cells only when it affects a category of genes that contains repetitive sequences within coding regions. After review of recent results reported in the literature, we underline here the fact that these mutations are observed in a number of different genes and with variable frequencies. Moreover, these mutations are proposed to be selected as recessive or dominant genetic events in these cancers, leading to different functional consequences. It is known that they occur in the context of a high background for instability in MSI-H tumors, sometimes with tissue specificity, and that mutations may also occur in other genes involved in the same signaling pathway and, therefore, have a putative synergistic effect. We believe the target gene concept should be reevaluated in light of these observations and that the selection for mutations in coding repeats should be considered the result of a complex process involving a number of different factors.

After the inactivation of MMR "caretaker" genes (83) , such as hMLH1 or hMSH2 in MSI-H tumors, all genes containing coding repeats can be considered equal target genes for mutations that are not repaired after inaccurate DNA replication. However, differences in the frequency of mutation do occur, and these are likely to be related to the length of the repeat and the nature of the relevant nucleotide sequence, as well as unknown influences from surrounding sequences (Fig. 2) . Different positive or negative selection pressures depending on the roles of the proteins encoded by the relevant genes could lead to the higher or lower mutation frequencies observed in the different genes. We propose to classify target genes into the following categories, thus expanding on the categories currently in use:

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Proposed model to explain the mutation frequencies observed in different classes of target genes for instability. The model takes into account the various selective pressures conferred by mutation.

(b) "Hibernator" genes. Because these genes do not have an important function in the affected cell type, their expression is simply down-regulated. Mutations in this category of genes are not expected to have phenotypic consequences. Even without negative or positive selection pressures for these mutations, the instability phenomenon at such sequences will be variable. The probability of mutation for these repeats will be influenced by sequence-dependent structural factors, as observed for noncoding nucleotide repeats, and reflects the background of instability characterizing MSI-H tumors.

(c) "Cooperator" genes. Alterations in these genes could be of functional significance if associated with other mutations in the same pathway, leading to a synergistic effect. FAS, APAF-1, and BCL10 genes belonging to the cell death pathway are examples of this category (22) . TCF-4 and AXIN could constitute another cooperator couple because both genes are involved in the same adenomatous polyposis coli/ß-catenin/TCF pathway. The mutation frequencies of cooperator genes may be highly variable, because selection pressures for such genetic events depend on the context in which they occur. Genes coding for MMR proteins and containing a coding repeat (e.g., hMSH3 and hMSH6) might constitute a subclass of cooperator genes (accelerator). Their inactivation as a second genetic event in the MMR pathway could increase the overall instability of MSI-H cancers and thus facilitate the accumulation of mutations in the gene repeats from all other categories. This has already been proposed for hMSH3 inactivation in MSI-H colorectal tumors (13 , 28) .

(d) "Transformator" genes. Mutations in these are considered as transforming events even when they occur in isolation. They have the highest observed frequency of mutation, because their alteration confers a positive growth advantage to the MSI-H cells in which they occur (Fig. 2) . The TGFßRII gene is the best known example of this category. Functional studies have demonstrated that mutation abrogates its tumor suppressor activity in MSI-H colon carcinoma cells (11) .

Similar to other tumorigenic pathways, these four categories of target genes could be mutated in a preferential order during MSI-H tumoral progression, even if their alterations are expected to be independent of each other (Fig. 3) . TGFßRII inactivation has thus been proposed as the earliest gene alteration in MSI-H gastrointestinal cancers after initial inactivation of the MMR system (28 , 84) . Other genes containing coding repeats might then accumulate mutations more or less rapidly, with possible acceleration of the mutational process when a second MMR gene is altered.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Evolution of mononucleotide repeat instability during MSI-H tumoral progression. Increasing mutation rates of the four different classes of genes containing coding repeat sequences are symbolized by survivor genes (1), hibernator genes (2), cooperator genes (3), and transformator genes (4).

As noted previously (28) , it is the number of altered target genes of all categories rather than their nature that should be examined in additional studies of MSI-H tumors. Alternatively, longer noncoding repeats, such as Bat-26 and Bat-25, should be examined because it has been shown that their stepwise shortening in these tumors correlates well with the number of mutations found within target genes (28) . Moreover, it should be borne in mind that in most cases, the MSI-H phenotype of sporadic tumors is because of epigenetic methylation of the hMLH1 promoter. It is likely that these tumors belong to the so-called CpG island methylator phenotype group and has many genes whose expression is down-regulated because of aberrant promoter methylation. Powerful technologies, such as cDNA macro and microarrays that permit simultaneous analysis of the expression of many genes, should lead to a more complete knowledge of the mutational and epigenetic events occurring in MSI-H tumors and their functional consequences.

	ACKNOWLEDGMENTS

 
We thank Dr. Barry Iacopetta for critical reading 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 A. D. was a recipient of a poste d’accueil from Institut National pour la Santé et la Recherche Médicale.

² To whom requests for reprints should be addressed, at Institut National pour la Santé et la Recherche Médicale 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; TCF, T-cell factor; HNPCC, hereditary nonpolyposis colorectal cancer syndrome; TGF-ßRII, type II receptor of transforming growth factor ß.

Received 7/ 6/01. Accepted 2/27/02.

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