[Replication error repair, microsatellites, and cancer].
Some common human tumors are characterized by inactivating alterations of mismatch repair (MMR) genes that lead to an inability to recognize and repair errors that occur during DNA replication. These alterations are either inherited in the so-called hereditary non polyposis colorectal cancer (HNPCC) syndrome or can occur sporadically in 10-15% of colorectal, gastric, or endometrial tumors. Because of their repetitive nature, microsatellite sequences are particularly prone to mutation in tumors with MMR deficiency. Thousands of microsatellite alterations accumulate in MMR deficient cancers and these are referred to as MSI-H tumors (high level of microsatellite instability). MSI-H tumors have different clinicopathological features compared to cancers without this phenotype, and the repertoire of genetic events involved in their tumoral progression is also thought to be different. Many of the genetic alterations observed in MSI-H tumors affect nucleotide repeat tracks contained within genes thought to have a putative oncogenic function. These alterations are believed to play an important role during MSI-H carcinogenesis, since they can be either inactivating or activating events that are selected for in a recessive or dominant manner. We provide here an overview of the genetic changes that occur in MSI-H tumors and that appear to constitute a new genetic mutator pathway leading a normal cell to become malignant.
Duval
Alex
A
Inserm U.434, CEPH, 27, rue Juliette Dodu, 75010 Paris, France. alex.duval@cephb.fr
Hamelin
Richard
R
D000251:Adenosine Triphosphatases / Q000502:physiology; D001419:Bacteria / Q000235:genetics; D001426:Bacterial Proteins; D020137:Base Pair Mismatch; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000502:physiology; D004706:Endodeoxyribonucleases / Q000502:physiology; D029968:Escherichia coli Proteins / Q000502:physiology; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008954:Models, Biological; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; D016296:Mutagenesis / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000473:pathology; D013045:Species Specificity
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C074770:MutL protein, E coli; D004706:Endodeoxyribonucleases; C059682:methyl-directed mismatch repair protein, E coli; D000251:Adenosine Triphosphatases; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli; D045643:DNA Repair Enzymes