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Landscape of BRAF transcript variants in human cancer
Maurizio S Podda1,2,3,4, Danilo Tatoni3,4, Gianluca Mattei5
1Institute of Clinical Physiology (IFC), CNR, Pisa, Italy.
Molecular Oncology
|May 26, 2025
Summary
The BRAF gene has two main variants, BRAF-204 and BRAF-220. BRAF-204 is more common in cancer, and a high ratio of BRAF-204 to BRAF-220 predicts poor outcomes in kidney cancer.
Area of Science:
- Oncology
- Bioinformatics
- Genomics
Background:
- The BRAFV600E mutant kinase is a key cancer driver and therapeutic target.
- Accurate discrimination and quantification of BRAF variants are crucial for cancer research.
- Public database annotations for BRAF variants have evolved, posing challenges.
Purpose of the Study:
- To investigate the evolution of BRAF-ref (BRAF-220) and BRAF-X1 (BRAF-204) annotations in public databases.
- To develop and apply a bioinformatics pipeline (IsoWorm) for discriminating and quantifying BRAF variants.
- To analyze the expression levels and clinical significance of BRAF variants in cancer.
Main Methods:
- Development of the IsoWorm bioinformatics pipeline for BRAF variant analysis.
- Analysis of >600 cancer cell lines and >1000 cancer tissue samples using IsoWorm.
- Reanalysis of TCGA data (>9000 cancer tissue samples) using FLIBase.
Main Results:
- BRAF-X1 (now BRAF-204) is highly abundant in human cancer, with expression 1.5-75 times greater than BRAF-ref (now BRAF-220).
- A high BRAF-204/BRAF-220 ratio is an independent prognostic factor for poor outcome in kidney renal papillary cell carcinoma (KIRP).
- In silico analyses confirm BRAF comprises two protein-coding transcript variants, with BRAF-204 being more highly expressed.
Conclusions:
- BRAF gene expression in cancer is a mix of two variants, BRAF-204 and BRAF-220, with BRAF-204 being predominant.
- The BRAF-204/BRAF-220 ratio has significant prognostic implications in specific cancer subtypes like KIRP.
- Further investigation into the molecular mechanisms, biological activities, druggability, and clinical relevance of BRAF-204 versus BRAF-220 is warranted.
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