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

• Published in: International journal of cancer Vol. 145; no. 9; pp. 2488 - 2495
• Main Authors: Osumi, Hiroki, Shinozaki, Eiji, Wakatsuki, Takeru, Suenaga, Mitsukuni, Ichimura, Takashi, Ogura, Mariko, Takahari, Daisuke, Ooki, Akira, Suzuki, Takeshi, Ota, Yumiko, Nakayama, Izuma, Chin, Keisho, Miki, Yoshio, Yamaguchi, Kensei
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2019; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Bioindicators; BRAFnon‐V600E mutation; BRAFV600E mutation; Cancer; Cell Differentiation - drug effects; Cell Differentiation - genetics; Class I Phosphatidylinositol 3-Kinases - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Epidermal growth factor receptors; ErbB Receptors - genetics; Exons; Female; Genotype; Genotyping; Histology; Homology; Humans; Kinases; Male; Medical research; Metastases; Middle Aged; Mutation; Mutation - genetics; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Patients; Phosphatidylinositol; Precision medicine; primary tumor location; Proto-Oncogene Proteins B-raf - genetics; Raf protein; Sarcoma; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Statistical analysis; BRAFV600E mutation; primary tumor location; BRAFnon-V600E mutation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32320

The Raf murine sarcoma viral oncogene homolog B (BRAFV600E) 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 BRAFnon‐V600E MTs remain unclear. Here, we evaluated the clinical characteristics of BRAFnon‐V600E MTs vs. those of other MTs in the EGFR signaling pathway, including BRAFV600E. 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 BRAFV600E/BRAFnon‐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 BRAFV600E/BRAFnon‐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 BRAFV600E 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 BRAFnon‐V600E MTs were a left‐sided primary tumor location and well‐differentiated histology. BRAFnon‐V600E MTs were relatively rare and showed different characteristics compared to the BRAFV600E MT. These results may contribute to future precision medicine. What's new? The BRAFV600E mutation in metastatic colorectal cancer (CRC) is a well‐known prognostic indicator and a negative predictive biomarker for anti‐epidermal growth factor receptor (EGFR) treatment. However, the clinical characteristics and significance of BRAFnon‐V600E mutations remain unclear. This study of CRC patients through the stage I to IV shows that BRAFnon‐V600E mutations are relatively rare, with a frequency of 1.7%. In contrast to the BRAFV600E mutation, BRAFnon‐V600E mutations correlated with left‐sided primary tumor location and well‐differentiated histology and did not serve as a poor prognostic factor. These results may contribute to future precision medicine.