DNA mismatch repair and cancer
Section snippets
DNA mismatch repair system in humans
The primary function of the postreplicative mismatch repair (MMR) is to eliminate base–base mismatches and insertion/deletion loops that arise as a consequence of DNA polymerase slippage during DNA synthesis (for recent reviews, see [1], [2], [3]). This system is highly conserved between species (Table 1). In humans, at least six different MMR proteins are required. For mismatch recognition, the MSH2 protein forms a heterodimer with two additional MMR proteins, MSH6 or MSH3, depending on
Inherited cancer susceptibility associated with defective MMR
Germline alteration of any one of the five human MMR genes, MSH2, MLH1, MSH6, PMS2 and PMS1, gives rise to hereditary nonpolyposis colon cancer (HNPCC) that accounts for 1–5% of all cases of colon cancer. Predisposed individuals from HNPCC families have a high lifetime risk of developing colorectal carcinoma (70–85%), endometrial carcinoma (50%), as well as certain other cancers (below 15%) [7], [8], collectively referred to as the “HNPCC tumor spectrum”. Germline mutations in MSH2 and MLH1 are
Causes and consequences of MSI in human tumors
Tumors from HNPCC patients show acquired variation in the number of short tandem repeat units contained within microsatellite sequences (MSI, microsatellite instability). This abnormality results from a failure to correct errors arising in these repeats during DNA replication, and occurs in approximately 15% of sporadic tumors from the colorectum and other organs as well [15]. Mutation rates in tumor cells with MMR deficiency are 100–1000-fold as compared to normal cells [16], [17]. Besides
Favorable prognosis associated with MMR-deficient tumors
MSI-positive tumors show aggressive histological features, but paradoxically a favorable outcome. In particular, a recent study [39] on a large series of young colorectal cancer patients demonstrated that MSI was associated with a significant survival advantage independently of all standard prognostic factors, including tumor stage. Furthermore, regardless of the depth of tumor invasion, these tumors had a decreased metastasizing potential. Enhanced immune surveillance offers one possible
Mouse models for tumor development in the context of MMR deficiency
To address the relationship between MMR defects and tumorigenesis, mice with mutations in the MutS and MutL homologs have been developed (Table 3). Unlike most HNPCC patients, mice heterozygous for MMR gene mutations do not show increased tumor formation. This is probably due to their short biological life span — tumors typically do not develop in humans until the average age of 40–45 years, either. Therefore, mice homozygous for MMR gene mutations have been used as models for HNPCC. While a
Other functions of the MMR system with cancer relevance
Recent findings indicate an important role for the MMR proteins in damage signaling and apoptosis. Apart from biosynthetic errors, MMR proteins can act on DNA damage caused by, for example, alkylating agents, including those used in cancer chemotherapy [52], heterocyclic amines, many of which are of dietary origin [53], or oxidation [54]. MMR-deficient cells are more resistant to the killing effects of alkylating agents as compared to their MMR-proficient counterparts [55]. In MMR-proficient
Therapeutic implications
Alkylation tolerance characteristic of MMR-deficient cells has direct implications for chemotherapy of HNPCC patients and other patients with MSI-positive tumors. Alkylating agents are not recommended because such therapy is not only expected to be ineffective but may even lead to the enrichment of tumor cells [65]. Another therapeutic area in which a profound knowledge of the MMR system is useful involves the application of the cyclo-oxygenase 2 (COX2) enzyme inhibitors, such as aspirin for
Concluding remarks
HNPCC provides a useful model system to study tumorigenesis driven by MMR deficiency. Despite an increasing knowledge about genetic and biochemical defects associated with this cancer syndrome, little is known about mechanisms that translate HNPCC genotype into its clinical phenotype. Why do some mutation carriers develop cancer already in their teens while other carriers of the same mutations remain healthy beyond 80 years of age? Why, in some individuals, the colorectum is affected while
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