Non-V600E BRAF mutations and EGFR signaling pathway in colorectal cancer

The Raf murine sarcoma viral oncogene homolog B (BRAF^V600E) mutation (MT) in metastatic colorectal cancer (CRC) is a well-known prognostic indicator and a negative predictive biomarker for antiepidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAF^non-V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAF^non-V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAF^V600E. Consecutive CRC patients in our institute from June 2012 to November 2013 were enrolled in our study. Multiplex genotyping of the EGFR pathway was performed with archival samples using a Luminex Assay for BRAF^V600E/BRAF^non-V600E, KRAS/NRAS exons 2–4, and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA). We analyzed correlations among the MT profiles, clinical data and primary tumor locations in CRC. All statistical analyses were performed using R software. CRC samples (824) from 374 (45.4%) male and 450 (54.6%) female patients were analyzed, of which 154 (18.7%), 202 (24.5%), 270 (32.8%) or 198 (24.0%) had Stages I, II, III or IV or recurrent CRC, respectively. The frequencies of BRAF^V600E/BRAF^non-V600E, KRAS (including exons 2–4), NRAS and PIK3CA MTs were 5.3/1.7, 41.4, 3.3 and 9.6%, respectively. The characteristics of patients with the BRAF^V600E MT were an age of ≥65 years old, a right-sided primary tumor location, poorly differentiated histology and an advanced disease stage. In contrast, the characteristics of patients with BRAF^non-V600E MTs were a left-sided primary tumor location and well-differentiated histology. BRAF^non-V600E MTs were relatively rare and showed different characteristics compared to the BRAF^V600E MT. These results may contribute to future precision medicine.