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Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Novel treatment-specific causal biomarkers for colorectal cancer by omics integration
Akram Yazdani1,2, Azam Yazdani3, Raul Mendez-Giraldez4
1Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.
Abstract:
While monoclonal antibody-based targeted therapies have substantially improved progression-free survival in cancer patients, the variability in individual responses poses a significant challenge in patient care. Therefore, identifying cancer subtypes and their associated biomarkers is required for assigning effective treatment. In this study, we integrated genotype and pre-treatment tissue RNA-seq data and identified biomarkers causally associated with the overall survival (OS) of colorectal cancer (CRC) patients treated with either cetuximab or bevacizumab. We performed enrichment analysis for specific consensus molecular subtypes (CMS) of CRC and evaluated differential expression of identified genes using paired tumor and normal tissue from an external cohort. In addition, we replicated the causal effect of these genes on OS using a validation cohort and assessed their association with The Cancer Genome Atlas Program data as an external cohort. One of the replicated findings was WDR62, whose overexpression shortened OS of patients treated with cetuximab. Enrichment of its overexpression in CMS1 and low expression in CMS4 suggests that patients with the CMS4 subtype may derive greater benefit from cetuximab. In summary, this study highlights the importance of integrating different omics data for identifying promising biomarkers specific to a treatment or a cancer subtype.
Insights
Identifying cancer biomarkers improves targeted therapy. This study integrated omics data to find genes affecting colorectal cancer patient survival, revealing WDR62 as a potential biomarker for cetuximab treatment effectiveness.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Monoclonal antibody therapies improve cancer survival but show response variability.
- Identifying cancer subtypes and biomarkers is crucial for personalized treatment strategies.
Purpose of the Study:
- To integrate genotype and RNA-seq data for identifying biomarkers associated with overall survival (OS) in colorectal cancer (CRC) patients treated with cetuximab or bevacizumab.
- To investigate the association of identified biomarkers with CRC consensus molecular subtypes (CMS).
Main Methods:
- Integrated genotype and pre-treatment tissue RNA-seq data.
- Performed enrichment analysis for CRC consensus molecular subtypes (CMS).
- Validated gene effects on OS using external cohorts and The Cancer Genome Atlas (TCGA) data.
Main Results:
- Identified biomarkers causally associated with OS in CRC patients receiving targeted therapies.
- Discovered that WDR62 overexpression negatively impacts OS in patients treated with cetuximab.
- Found WDR62 overexpression enriched in CMS1 and low expression in CMS4, suggesting CMS4 patients may benefit more from cetuximab.
Conclusions:
- Integrating multi-omics data is vital for discovering treatment-specific and cancer subtype-specific biomarkers.
- WDR62 may serve as a predictive biomarker for cetuximab therapy in specific colorectal cancer subtypes.
- Findings support personalized treatment approaches based on molecular profiling and subtype classification.
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