Microsatellite instability in human cancer: a prognostic marker for chemotherapy?
The majority of tumors associated with the nonpolyposis form of familial colorectal cancer (HNPCC) shows a specific form of genetic instability which is manifested by length alterations of mono- or dinucleotide repeat sequences [e.g., (A)n or (CA)n]. This phenomenon was termed the RER+ (replication error-positive) phenotype, MSI or MIN (microsatellite instability), and found to result from defects in the cells' DNA mismatch repair system. This system recognizes and restores misincorporated bases or slippage errors which frequently occur during DNA replication. Loss of DNA mismatch repair therefore strongly accelerates the evolutionary process of mutagenesis and selection which underlies the development of cancer. In addition to mutation avoidance, DNA mismatch repair also plays a crucial role in the toxicity of a number of DNA-damaging drugs that are used in cancer chemotherapy. In experimental systems, mismatch-repair-deficient cells are highly tolerant to the methylating chemotherapeutic drugs streptozocin and temozolomide and, albeit to a lesser extent, to cisplatin and doxorubicin. These drugs are therefore expected to be less effective on mismatch-repair-deficient tumors in humans. MIN was also found in a substantial portion of sporadic (nonfamilial) human tumors. However, in many cases the extent of microsatellite instability was not as dramatic as found in HNPCC-related tumors and the underlying genetic defect is unclear. Therefore, while the mismatch repair status of tumors may become an important determinant in the choice of chemotherapeutic intervention, the significance of MIN in sporadic cancer remains elusive.
Claij
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Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
te Riele
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D020137:Base Pair Mismatch / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D005819:Genetic Markers; D002945:Cisplatin