Longitudinal change of genetic variations in cetuximab-treated metastatic colorectal cancer
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Updated: Oct 26, 2025
Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Sun Young Kim1, Kwoneel Kim2, Su Han Cho3
1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Abstract:
Recurrent gene mutations and copy number alterations in cancer patients are presumably associated with resistance to targeted therapy. In the present study, we assessed the gene mutations and copy number alterations that recurrently occurred in cetuximab-treated patients with metastatic colorectal cancer (mCRC). Targeted next-generation sequencing was performed in the tumor samples obtained pre- and postcetuximab treatment to assess the variations that occurred during cetuximab treatment. Moreover, we identified the emergent gene mutations (CDK6, EPHA3, ERCC2, MYC, PCMTD1, PIK3CA, PRIM2, RICTOR, and ZNRF3) and copy number alterations (ARAF, BCL2, BRCA2, EGFR, MYC, and SMAD4) that were recurrently observed only in postprogression samples and not in pretreatment or posttreatment samples from patients revealing clinical response. Furthermore, to identify the feasible candidate variations implicated in treatment resistance, we examined the variants with clonal expansion during treatment and discovered PCBP1 as a variant associated with posttreatment progression. Various recurrent mutations were enriched in the TGF-beta signaling pathway. Collectively, we identified recurrent variations in mCRC samples exhibiting post-cetuximab progression. Additionally, future studies are required to evaluate the therapeutic potential of these variations.
Insights
This study identified new gene mutations and copy number alterations in metastatic colorectal cancer (mCRC) that emerge during cetuximab treatment, potentially causing resistance. These findings offer insights into treatment resistance mechanisms for mCRC patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Targeted therapies are crucial for metastatic colorectal cancer (mCRC).
- Gene mutations and copy number alterations are linked to treatment resistance.
- Cetuximab is a targeted therapy used for mCRC.
Purpose of the Study:
- To identify recurrent gene mutations and copy number alterations associated with cetuximab resistance in mCRC.
- To understand the genetic changes occurring during cetuximab treatment.
- To discover potential biomarkers for treatment resistance.
Main Methods:
- Targeted next-generation sequencing of tumor samples from mCRC patients before and after cetuximab treatment.
- Analysis of emergent gene mutations and copy number alterations in postprogression samples.
- Investigation of variants with clonal expansion during treatment.
Main Results:
- Identified emergent mutations (e.g., CDK6, PIK3CA, MYC) and copy number alterations (e.g., EGFR, MYC, SMAD4) in postprogression samples.
- Discovered PCBP1 as a variant associated with posttreatment progression.
- Found enrichment of recurrent mutations in the TGF-beta signaling pathway.
Conclusions:
- Recurrent genetic variations are associated with cetuximab resistance in mCRC.
- Emergent mutations and copy number alterations provide insights into resistance mechanisms.
- Further research is needed to explore the therapeutic potential of identified variations.
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