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RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis

Daniel Iglesias1, Antonia M Fernández-Peralta, Nargisse Nejda

  • 1Unidad de Genética, Departamento de Biología, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.

Cancer Genetics and Cytogenetics
|June 2, 2006
PubMed

Insights

The gene RIS1 (Ras-induced senescence 1) is frequently mutated in high-frequency microsatellite instability (MSI-H) colorectal cancers and linked to poorer prognosis in MSI-L tumors, identifying it as a target gene in the mutator pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Microsatellite instability (MSI) and mismatch repair (MMR) system alterations are key in colorectal cancer (CRC) development.
  • The mutator pathway is implicated in CRC pathogenesis.
  • Understanding genetic alterations in MSI tumors is crucial for targeted therapies.

Purpose of the Study:

  • To analyze the gene RIS1 (Ras-induced senescence 1) in colorectal cancer.
  • To investigate the relationship between RIS1 alterations, loss of heterozygosity (LOH), and frameshift mutations.
  • To compare RIS1 status with genetic and clinicopathological variables in CRC patients.

Main Methods:

  • Analysis of RIS1 gene for LOH and frameshift mutations in trinucleotide repeats.
  • Correlation of RIS1 alterations with MSI status (MSI-H, MSI-L).
  • Comparison of RIS1 mutations with mutations in BAX, TGFBR2, and epigenetic silencing of MLH1.
  • Prognostic analysis based on RIS1 mutation status and MSI levels.

Main Results:

  • RIS1 did not show LOH in informative tumors.
  • Frameshift mutations in RIS1 were found in 43.8% of MSI-H tumors.
  • RIS1 alterations correlated with BAX and TGFBR2 mutations and MLH1 silencing in MSI-H tumors.
  • RIS1 mutations in MSI-L tumors were associated with a significantly worse prognosis, including metastasis and reduced survival.

Conclusions:

  • RIS1 is a target gene in the colorectal cancer mutator pathway, according to Bethesda criteria.
  • RIS1 alterations are frequent in MSI-H CRC and impact prognosis.
  • RIS1 mutations may serve as a prognostic biomarker in MSI-L colorectal cancer.

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