Landscape of BRAF transcript variants in human cancer

Abstract

The BRAFV600E mutant kinase is widely studied as a cancer driver and therapeutic target. Here, we investigated how the annotation of the BRAF‐reference (ref) and BRAF‐X1 variants has evolved in public databases and addressed challenges posed by their discrimination and quantification from short‐read sequencing. We built IsoWorm, a bioinformatic pipeline tailored to discriminate and quantify BRAF variants, and employed it to analyze > 600 cancer cell lines and > 1000 cancer tissue samples. Using FLIBase, we reanalyzed TCGA data from > 9000 cancer tissue samples. We consistently found that BRAF‐X1 (now BRAF‐204) is very abundant in human cancer and its expression is 1.5–75 times greater than that of BRAF‐ref (now BRAF‐220). Crucially, we identified KIRP‐kidney renal papillary cell carcinoma as a cancer subtype in which a high BRAF‐204/BRAF‐220 ratio is an independent prognostic factor of poor outcome. Our in silico analyses establish BRAF as a mix of two protein‐coding transcript variants, with BRAF‐204 being more highly expressed than BRAF‐220. These findings prompt us to undertake the systematic benchmarking of BRAF‐204 against BRAF‐220 in terms of molecular mechanisms, biological activities, druggability, and clinical relevance.