Abstracts
Résumé
La découverte d’un lien entre la survenue de certains cancers et l’existence de mutations des gènes du système de réparation des erreurs de réplication de l’ADN (système MMR) a récemment ouvert de nouveaux horizons dans l’étude de la carcinogenèse chez l’homme. Ces tumeurs (cancers MSI-H) sont avant-tout caractérisées par une instabilité génétique objectivée au niveau des séquences répétées microsatellites de l’ADN. Secondairement à l’inactivation d’un gène MMR, qui n’est pas reconnue en soi comme un événement transformant, d’autres altérations génétiques vont être accumulées conduisant à la transformation d’une cellule MSI-H. Dans ces cancers MSI-H, les gènes connus pour être fréquemment mutés dans d’autres types tumoraux adoptant les mêmes localisations, ne sont que rarement altérés. En revanche, d’autres gènes contenant des microsatellites dans leur séquence codante sont décrits comme des cibles privilégiées de mutations au niveau de telles répétitions. Ainsi, en accord avec le type très particulier d’instabilité génétique qui les caractérise, la progression des cancers MSI-H semble liée en grande partie à l’accumulation de nombreuses altérations affectant ces gènes, appelés gènes cibles de l’instabilité génétique de ces tumeurs.
Summary
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.
Appendices
Références
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