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© 2003 American Society for Clinical Oncology Role of DNA Mismatch Repair Defects in the Pathogenesis of Human Cancer
From the Department of Medical Genetics, University of Helsinki, Finland; and Division of Human Cancer Genetics, The Ohio State University, Columbus, OH. Address reprint requests to Päivi Peltomäki, MD, Department of Medical Genetics, Biomedicum Helsinki, P.O. Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Finland; email: paivi.peltomaki{at}helsinki.fi.
The DNA mismatch repair (MMR) system is necessary for the maintenance of genomic stability. In a broad sense, all main functions of the MMR system, including the correction of biosynthetic errors, DNA damage surveillance, and prevention of recombination between nonidentical sequences serve this important purpose. Failure to accomplish these functions may lead to cancer. It is therefore not surprising that inherited defects in the MMR system underlie one of the most prevalent cancer syndromes in humans, hereditary nonpolyposis colon cancer (HNPCC). In addition, acquired defects of the same system may account for 15% to 25%, or even a higher percentage, of sporadic cancers of different organs of the "HNPCC spectrum," including the colon and rectum, uterine endometrium, stomach, and ovaries. Recent studies indicate that the MMR genes may be involved in the pathogenesis of even a broader spectrum of tumors in one way or another. An updated review of the different features of the human MMR system will be provided, with the emphasis on their implications in cancer development.
The primary function of the MMR system is to eliminate single-base mismatches and insertion-deletion loops that may arise during DNA replication.1–5 Insertion-deletion loops result from gains or losses of short repeat units within microsatellite sequences, also known as microsatellite instability (MSI). At least six different MMR proteins are required. For mismatch recognition, the MSH2 protein forms a heterodimer with either MSH6 or MSH3 depending on the type of lesion to be repaired (MSH6 is required for the correction of single-base mispairs, whereas both MSH3 and MSH6 may contribute to the correction of insertion-deletion loops). A heterodimer of MLH1 and PMS2 coordinates the interplay between the mismatch recognition complex and other proteins necessary for MMR. These additional proteins may include at least exonuclease 1 (EXO1), possibly helicase(s), proliferating cell nuclear antigen (PCNA), single-stranded DNA-binding protein (RPA), and DNA polymerases  and  . In addition to PMS2, MLH1 may heterodimerize with two additional proteins, MLH3 and PMS1. Recent observations indicate that PMS2 is required for the correction of single-base mismatches, and PMS2 and MLH3 both contribute to the correction of insertion-deletion loops, whereas the role of PMS1 in MMR awaits further research. Additional homologs of the human MMR proteins are known that are required for functions other than MMR. These proteins include MSH4 and MSH5 that are necessary for meiotic (and possibly mitotic) recombination but are not presumed to participate in MMR.
Germline mutations of human MMR genes cause susceptibility to hereditary nonpolyposis colon cancer (HNPCC), one of the most common cancer syndromes in humans. An excess of colon cancer and a defined spectrum of extracolonic cancers, diagnosed at an early age and transmitted as an autosomal dominant trait, constitute the clinical definition of the syndrome. The international diagnostic criteria for HNPCC, known as "Amsterdam criteria I" (based on colorectal cancer)6 and "Amsterdam criteria II" (based on cancers of the colon and rectum, endometrium, small bowel, ureter, and renal pelvis),7 rely on these clinical hallmarks. A molecular definition of the syndrome requires the demonstration of a heritable defect in MMR. As expected, a majority of families that fulfill the clinical criteria, especially the Amsterdam criteria I (the most stringent set of criteria), also meet the molecular definition of the syndrome. Thus, germline mutations in one of four major HNPCC-associated MMR genes, MLH1, MSH2, MSH6, and PMS2, are detected in up to 70% to 80% of such families.8–11 To date, more than 400 different predisposing MMR gene mutations are known, with  50% affecting MLH1, 40% MSH2, and 10% MSH6 (International Collaborative Group on HNPCC Web site, available at http://www.nfdht.nl). The share of PMS2 is less than 5%. The newly identified human MMR gene MLH3 may account for a small percentage of HNPCC or HNPCC-like families,12 even though more data are needed about the prevalence, pathogenicity, and clinical correlations of such mutations. A germline mutation in PMS1 was originally reported in an HNPCC-like family.13 However, reexamination of the same family revealed the presence of an additional MSH2 mutation that cosegregated with colon cancer in the family, whereas the PMS1 mutation did not.14 Therefore, there is presently no evidence of PMS1 as an HNPCC predisposition gene, even though the possibility that this gene is implicated in the pathogenesis of (or susceptibility to) non-HNPCC cancers cannot be excluded. Finally, germline variants have been reported to occur in genes coding for two additional components of MMR, exonuclease 1 (EXO1)15 and DNA polymerase .16 The available data are too limited to allow any reliable assessment of their role in HNPCC predisposition (and in the case of DNA polymerase , no family studies have been conducted).
Table 1
Based on clinical criteria only, the estimated incidence of HNPCC varies between 0.5%25 and 13%26 of the total colorectal cancer burden. Strictly molecular approaches based on the identification of germline mutation carriers among newly diagnosed colorectal cancer patients whose tumors showed MSI have arrived at lower estimates (0.3% to 3% of the total colorectal cancer burden27–32). Similar molecular approaches on consecutive patients with endometrial cancer, the second most common cancer in HNPCC, have arrived at comparable frequencies of MMR gene germline mutation carriers (0.8% to 1.4% among all patients33,34). These molecular estimates are likely to underestimate the frequency of HNPCC to some degree; for example, by focusing on the MLH1 and MSH2 genes only. Among 47 different germline mutations identified in the eight consecutive series cited above,27–34 38 (81%) affect MLH1, whereas nine (18%) affect MSH2.
MSI, the hallmark of HNPCC, occurs in approximately 15% to 25% of sporadic tumors of the colorectum and other organs as well. According to international criteria, a high degree of MSI (MSI-H) is defined as instability at two or more of five loci or  30% to 40% of all microsatellite loci studied, whereas instability at fewer loci is referred to as MSI-low (MSI-L).35 Colorectal cancers with MSI-H encompass a group of tumors with a predilection for the proximal colon, that have diploid DNA content, that are high grade, and that are associated with female sex; patients with these tumors have better survival.36–39 These features distinguish MSI-H tumors from those without widespread MSI; that is, MSI-L or microsatellite-stable (MSS) tumors.
Table 2
Whereas the MSI-L subset of colon cancers is as equally prevalent as the MSI-H group, immunohistochemical and mutation studies have found no involvement of MLH1, MSH2, MSH6, or MSH3 in the former tumors.30,51,52 The clinicopathological features do not seem to distinguish this group from MSS colon cancers, either.51 Therefore, it is not settled whether or not MSI-L tumors should be considered separate from MSS tumors, and conclusions drawn from different studies are in part conflicting. Some researchers emphasize important distinguishing features between MSI-H, MSI-L, and MSS tumors.53–56 In particular, it has been suggested that DNA methylation may play an important role in the determination of MSI-H versus MSI-L phenotype through selective inactivation of MLH1 versus MGMT (encoding the O-6-methylguanine DNA methyltransferase), respectively. It is obvious that the number of microsatellite markers used is crucial for accurate MSI status assignment, and the five markers included in the consensus Bethesda panel35 may not be sufficient. Thus, in comparison with results obtained with a total of 148 polymorphic microsatellite markers, Anderson et al57 reported false-positive rates of 13% for the diagnosis of MSI-L, if the number of assays was limited to five. Similarly, the investigation of Laiho et al58 underlines the absence of clear-cut molecular differences between MSI-L and MSS groups of colorectal cancers. More studies are clearly needed for a more accurate and meaningful classification of tumors according to the degree of MSI.
MSI occurs in a substantial proportion (2% to 50% of tumors35) among non-HNPCC cancers (eg, cancers of the breast, prostate, and lung). On the basis of the proportion of unstable markers, categories MSS, MSI-L, and MSI-H can be distinguished in these cancers in analogy to HNPCC cancers. However, the type of repeats involved in non-HNPCC cancers is different in that di-, tri-, and tetranucleotide rather than mononucleotide repeats are typically affected.35 Thus, whereas in colorectal cancers the mononucleotide repeat marker BAT26 alone seems sufficient for MSI determination,59 this is not the case among cancers not belonging to the HNPCC spectrum.60,61 Apart from the type of unstable markers, another difference between non-HNPCC and HNPCC tumors concerns the presentation of instability: Instead of a "ladder" type instability characteristic of HNPCC tumors, non-HNPCC tumors often show a few discrete extra bands or band shifts.61,62
In non-HNPCC cancers, the etiology of MSI seems heterogeneous and may or may not be associated with a defect in the MMR system. Table 3
Studies of adjacent normal mucosa from patients (especially elderly ones) with colon cancer have revealed a relatively frequent hypermethylation of the MLH1 promoter accompanied by the loss of the MLH1 protein.49,50 Despite an inferred MMR defect in these cells, their phenotype appears normal, and no MSI is detectable by conventional techniques, which is consistent with the absence of a clonal change.49 However, the MMR gene defect increases the risk of malignant transformation of these cells, which may ultimately result from the disruption of one or several anticarcinogenic functions of the MMR genes. First, malfunction of the MMR system is associated with decreased genomic stability, which may manifest itself as highly elevated rates of subtle mutations (MSI) throughout the genome.70,71 Second, although MMR-deficient cells typically have a diploid or near-diploid DNA content, loss of heterology-dependent suppression of recombination in these cells may promote gene conversion and expose tumor suppressor genes in analogy to loss of heterozygosity,72 or allow chromosomal translocations to occur.73 Furthermore, increased mutational inactivation of genes involved in DNA double-strand break repair74,75 may contribute to an elevated degree of chromosomal aberrations in MMR-deficient cells. Third, besides anonymous microsatellite sequences, critical genes may be affected with mutations, conferring a growth advantage on the cells. Typical "target" genes (that are different in different tissues) include those involved in growth suppression,76 apoptosis,77 or signal transduction.78,79 Fourth, there is evidence that failed protection against endogenous or exogenous DNA damage and the ensuing persistence of mutagenic or premutagenic lesions may contribute to genomic instability/MSI in intestinal cells.80–82
DNA mismatch repair defects are common in several cancers as inferred from the occurrence of MSI. MSI analysis and/or immunohistochemical staining for MMR protein expression offer useful preliminary tests for MMR gene involvement.83 The detection of a MMR defect may provide an important piece of information to guide the clinical management of the patients. For example, malfunction of the MMR system may modify the response to cytotoxic drugs: cancers with MSI may be particularly sensitive to fluorouracil and other antimetabolites,84,85 whereas the same tumors show increased resistance to alkylating agents.86 It is speculated that fluorouracil, which acts as a competitive inhibitor for substrates critical for DNA synthesis, may work in concert with MMR deficiency and enhance apoptosis in these cells.84 However, a functional mismatch repair system is believed to be a prerequisite for the cytotoxicity of alkylating agents, based on its role as a detector of damaged DNA. The resistance of MMR-deficient cells to alkylating agents is thought to result from the failing detection of alkylation adducts and impaired induction of apoptosis.87 In only a small percentage (perhaps 10% of consecutive colon cancer patients with MSI-H27–32) is the MMR defect hereditary. However, the identification of this subgroup is important, given the need and documented benefits88 of regular cancer surveillance for both the patient and the patient’s close relatives. Finally, it cannot be excluded that the MMR system plays a role in the development of some microsatellite-stable cancers as well, through functions other than mismatch correction. Increased knowledge of the properties of the MMR system and its connections to other biologic pathways is essential to better understand the fundamental mechanisms of cancer development and to identify targets for preventive and therapeutic interventions.
Supported by grants from the Sigrid Juselius Foundation, Academy of Finland, Finnish Cancer Foundation, and the National Institutes of Health (CA82282).
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P, Glavac D: Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population. J Med Genet 37:533–536, 2000
