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Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes
1Institut National de la Santé et de la Recherche Médicale U434: CEPH, 75010 Paris, France.
Abstract:
Because the discovery of a link between mismatch repair deficiency and sporadic or inherited human cancers characterized by microsatellite instability (MSI-H tumors), genes containing coding repeat sequences have been found to be mutated at these repeats in MSI-H tumors from different primary sites as reported in the present review. Accumulation of such alterations appears to be the main molecular mechanism by which MSI-H cells accumulate functional changes with putative oncogenic effects. These mutations occur in many genes at variable frequencies. They can affect genes with a putative role in human carcinogenesis involved in different or similar pathways and are thus thought to be inactivating or activating events selected for in these cancers in a recessive or dominant manner. However, because of the high level of instability characterizing these cancers, they are also likely to occur in genes without any expected role in MSI-H carcinogenesis. In light of these recent data, the concept of target genes for instability and their possible role in MSI-H cancers is reconsidered here.
Insights
Microsatellite instability (MSI-H) in human cancers results from mismatch repair deficiency. Mutations in repeat sequences within genes are a key mechanism driving cancer development in MSI-H tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mismatch repair deficiency is linked to human cancers with microsatellite instability (MSI-H).
- Genes with coding repeat sequences are frequently mutated in MSI-H tumors.
- These mutations are a primary molecular mechanism for functional changes in MSI-H cells.
Purpose of the Study:
- To review and reconsider the concept of target genes for microsatellite instability.
- To explore the role of these target genes in MSI-H cancers.
Main Methods:
- Literature review of studies on MSI-H tumors and gene mutations.
- Analysis of mutation frequencies and affected pathways in MSI-H cancers.
Main Results:
- Mutations in repeat sequences occur in various genes within MSI-H tumors.
- These mutations can affect genes involved in carcinogenesis, leading to inactivating or activating events.
- Instability may also lead to mutations in genes not directly implicated in MSI-H carcinogenesis.
Conclusions:
- The accumulation of mutations in repeat sequences is a critical driver of MSI-H tumorigenesis.
- The definition and role of 'target genes' in MSI-H cancers require re-evaluation.
- Further research is needed to understand the full spectrum of genes affected by microsatellite instability.