Abstract
Different genetic aberrations of BRAF have been reported in various malignancies. BRAF is member of the RAS/RAF/MEK/ERK pathway and constitutive activity of this pathway can lead to increased cellular growth, invasion, and metastasis. The most common activating BRAF mutation in colorectal cancer is the V600E mutation, which is present in 5–15% of all tumors, and up to 80% of tumors with high microsatellite instability (MSI) harbor this mutation. BRAF mutation is associated with proximal location, higher age, female gender, MSI-H, high grade, and mucinous histology, and is a marker of poor prognosis in colorectal cancer. The role of BRAF mutation as a predictive marker in respect of EGFR targeted treatments is controversial. BRAF V600 selective inhibitors have been approved for the treatment of V600 mutation positive metastatic melanoma, but the response rates in colorectal cancer are poor. This might be due to innate resistance mechanisms of colorectal cancers against the treatment solely targeting BRAF. To overcome resistance the combination of treatments, simultaneous inhibition of BRAF and MEK or PI3K/mTOR, might emerge as a successful therapeutic concept.
Highlights
BRAF (v-raf murine sarcoma viral oncogene homolog B1) is a serine/threonine protein kinase of the RAF family
High microsatellite instability is associated with a higher number of harvested lymph nodes [28, 29], and a recent study reported that BRAF V600E mutation was associated with a lower node harvest in the MSI-H group in colon cancer [30]
BRAF V600E mutation is a marker of poor prognosis in colorectal cancer
Summary
BRAF (v-raf murine sarcoma viral oncogene homolog B1) is a serine/threonine protein kinase of the RAF family. RAF proteins are kinases in RAS/RAF/MEK/ERK pathway. In roughly 75% of the cases, colorectal cancer develops through chromosomal instability pathway, and these tumors can harbor APC mutations (>90%), KRAS mutations (50%), TP53 mutations (70%), and allelic loss of 18q (80%) [9]. DETECTION OF BRAF MUTATION IN COLORECTAL CANCER Until recently the detection of BRAF mutations was performed with Sanger sequencing or PCR-based assays. These methods require representative amount of malignant cells and extraction of the DNA. For specimens with a low content of tumor tissue, the DNA based protocols might not be sensitive enough to detect the BRAF mutations. Colorectal cancer has been analyzed with the BRAF V600E mutation specific antibody and most studies find high sensitivities and specificities (98.8–100%) in comparison www.frontiersin.org
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