Introduction

Microsatellites (MS) are repetitive stretches of genomic DNA consisting of mono-, di-, tri-, tetra-, and pentanu-cleotide repeats. Tens of thousands of MS are distributed throughout the genome. The length of MS repeats in individuals of a species tends to be highly polymorphic making them suitable as genetic markers. For this reason, MS analysis has become a valuable tool in forensic medicine, paternity testing, tissue typing, and molecular diagnostics. Because of their simple sequence structure, MS are usually located in regions of DNA that are not transcribed or translated. However, a growing number of coding mono-, tri-, and tetranucleotide repeats are reported to be involved in cancer or neurodegenerative disorders. Because of their repetitive nature, MS sequences are prone to alteration during DNA replication as a result of polymerase slippage and/or misalignment of template strands. In normal cells the mismatch repair (MMR) system detects and repairs small DNA alterations such as missense mutations and small insertions and deletions. A defective MMR system may result in shortened or extended microsatellite sequences (microsatellite instability, MSI), ultimately accumulating genomewide mutations affecting fundamental cellular processes such as signal transduction, cell growth, apoptosis, or DNA repair.

Microsatellite instability occurs in about 15% of all colorectal cancers (CRC) and is a hallmark of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. Inactivating germline mutations in MMR genes will predispose patients of HNPCC families to colorectal and other cancers (e.g., tumors of the endometrium, ovary or upper urinary tract). Promoter hypermethylation of MMR genes may epigenetically cause MSI in sporadic CRC. Microsatellite instability tumors exhibiting such ''mutator phenotype'' differ from microsatellite-stable (MSS) tumors in their molecular, histopathological, and clinical characteristics. Microsatellite-stable tumors are characterized by aneuploidy and frequent large chromosomal deletions or amplifications, a feature referred to as chromosomal instability (CIN). In contrast, colorectal MSI tumors are commonly diploid with few chromosomal alterations. They typically arise in the right colon, are poorly differentiated, are of mucinous type, and show extensive intra- and peritumoral lymphocytic infiltration. Patients with MSI CRC tend to have a favorable clinical prognosis and are reported to respond better to chemo-therapeutical treatment than patients with MSS CRCs.

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