Atypical RAS Mutations in Metastatic Colorectal Cancer.
Filippo Pietrantonio1,2, Rona Yaeger3, Alexa B Schrock4
1Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
JCO Precision Oncology
|February 1, 2022
Summary
Atypical RAS (At-RAS) mutations in metastatic colorectal cancer (mCRC) are rare but may indicate RAS pathway activation. These mutations show similar overall survival to typical RAS mutations and are linked to POLE exonuclease domain mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic colorectal cancer (mCRC) is a significant health concern.
- RAS mutations are key drivers in mCRC, influencing treatment decisions.
- Uncommon atypical RAS (At-RAS) mutations present unique molecular characteristics.
Purpose of the Study:
- To characterize the clinical and molecular features of mCRCs with At-RAS mutations.
- To investigate the association of At-RAS mutations with tumor mutational burden (TMB) and microsatellite instability (MSI).
- To evaluate the impact of At-RAS mutations on patient overall survival (OS).
Main Methods:
- Multi-center study utilizing next-generation sequencing data from five sources.
- Retrieved 175 At-RAS mutated cases for analysis.
- Clinical and molecular data were analyzed for correlations with mutation status and patient outcomes.
Main Results:
- At-RAS mutations were found in 0.9% of 18,270 mCRCs.
- A subset of At-RAS tumors exhibited microsatellite instability-high (MSI-H) or high TMB.
- Patients with At-RAS mutations had a median OS of 32.3 months, comparable to typical RAS mutations.
- Co-occurrence of POLE exonuclease domain mutations was noted in At-RAS tumors.
Conclusions:
- At-RAS mutations serve as potential biomarkers for RAS pathway activation in mCRC.
- These mutations are associated with a higher frequency of POLE exonuclease domain mutations.
- Understanding At-RAS mutations is crucial for refining prognostic and predictive models in mCRC.
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