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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
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Association of KRAS Mutation and Gene Pathways in Colorectal Carcinoma: A Transcriptome- and Methylome-Wide Study and

Farzana Jasmine1, Armando Almazan1, Yuliia Khamkevych1

  • 1Institute for Population and Precision Health, Biological Sciences Division, The University of Chicago, Chicago, IL 60637, USA.

International Journal of Molecular Sciences
|August 10, 2024
PubMed

Insights

KRAS mutations in colorectal cancer (CRC) correlate with significant gene pathway dysregulation and methylation changes. This suggests potential targeted therapies, including anti-CDKN2A treatment with Villosol for KRAS-mutant CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Kirsten Rat Sarcoma (KRAS) is the most frequently mutated oncogene in colorectal carcinoma (CRC).
  • Previous research established links between microsatellite instability (MSI), DNA promoter methylation, and gene expression in CRC.
  • Understanding KRAS mutation impacts on gene expression and methylation is crucial for advancing precision medicine in CRC.

Purpose of the Study:

  • To investigate associations between KRAS mutation status, gene expression profiles, and DNA methylation patterns in colorectal cancer.
  • To identify potential therapeutic targets and biomarkers for precision medicine approaches in KRAS-mutant CRC.

Main Methods:

  • Genome-wide gene expression analysis was performed on paired CRC tumor and adjacent healthy tissues.
  • Genome-wide DNA methylation profiling was conducted on the same paired tissue samples.
  • Correlations between KRAS mutation, gene expression, and methylation status were statistically analyzed.

Main Results:

  • Colorectal tumors with KRAS mutations exhibited significantly greater dysregulation across major gene pathways compared to tumors without mutations.
  • Gene pathway dysregulation (up-regulation and down-regulation) strongly correlated with corresponding DNA hypomethylation and hypermethylation, respectively.
  • Upregulation of CDKN2A was more pronounced in KRAS-mutant CRC tumors, correlating with 5-FU resistance in cell line studies.
  • Proteasome pathway genes were markedly upregulated in CRC, particularly in tumors with KRAS mutation and MSI.

Conclusions:

  • KRAS mutation status significantly influences global gene expression and methylation landscapes in colorectal cancer.
  • CDKN2A upregulation in KRAS-mutant CRC suggests potential efficacy of anti-CDKN2A therapies like Villosol.
  • The observed proteasome pathway dysregulation may indicate a role for proteasome inhibitors in specific CRC patient subsets.
Keywords:
CDKN2AEGFRKRAS mutationMSIVEGFVillosolcolorectal carcinomaproteasome inhibitor

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