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.