Recent studies have revealed frequent activating mutations of the gene for BRAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies.
On the contrary, no mutation was identified in BRAF exon 15 for either endometrial or cervical cancer samples at position V600, which represents the most frequently mutated site of BRAF in human cancer.
Mutations of signaling components, such as EGFR (c-erbB1), Ras, and B-Raf, have been shown to play roles in the genesis of human cancer, while point mutation of ERK has not been reported.
Activating mutations of the BRAF gene are the most common genetic alterations in papillary thyroid carcinomas (PTCs) and the T1799A transversion, resulting in BRAFV600E, appeared virtually unique in this cancer type.
The very recent discovery of B-RAF point mutations as the most prevalent genetic alteration in papillary thyroid carcinoma has revolutionized the molecular knowledge of thyroid malignancies.
The BRAF mutation was found in all the individual cancers in 29 (47.5%) of the patients (all-positive group) and the mutation was absent in all the individual cancers in 8 (13.1%) patients (all-negative group).
In this review we have assessed the potential utility of a molecular test for somatically acquired mutations in B-RAF using thyroid malignancy as a model system according to 3 fundamental questions: would a test enhance our ability to distinguish benign from malignant, would a test unveil a risk factor not otherwise known, and would detecting a mutation enable a therapeutic option specific to those patients who carry the mutation?
In conclusion, our results suggest that BRAF-V600E mutations are mainly involved in colorectal cancer families characterized by an increased risk of other common malignancies.
These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor.
The majority of the mutations in BRAF in cancer are activating, but rare mutants that cannot activate MEK have provided new insight into RAF signalling networks that exist in cancer and normal cells.
The Ras signaling pathway controls important cellular responses to growth factors, and somatic mutations in RAS genes and other components of the Ras pathway, such as PTPN11 (encoding the protein-tyrosine phosphatase SHP-2) and BRAF, are found in human malignancies.
In sum, we were able to screen up to nine cancer samples on a single BRAF microarray (three per CDH on three regions per slide), indicating that this method may dramatically decrease the experimental time, cost, and effort of mutation detection in BRAF and other genes amenable to microarray analysis.
Recent studies have revealed frequent activating mutations of the gene for B-RAF, an effector of Ras protein in the mitogen-activated protein kinase pathway, in several malignancies, including melanoma, thyroid, colorectal and ovarian cancer.
Furthermore, a particular attention is focused to the role of pre-operative detection of BRAF mutation in the FNAB specimens of thyroid nodules and to the use of this gene as target for an effective cancer therapy.
Ras effectors also contribute to cancer, as mutations occur in Ras effectors, notably B-Raf and PI3-K, and drugs blocking elements of these pathways are in clinical development.
Here, we discuss recent progress, using preclinical models and clinical studies, to resolve the controversy of whether B-Raf would be a good therapeutic target for melanoma and other malignancies.
As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation, it may provide possible diagnostic and therapeutic targets in human malignant tumors.
Furthermore, it will also provide insight to the normal function of B-Raf and MEK, and contribute to the knowledge of the role of the MAPK pathway in cancer.
BRAF-activating mutations have been reported in several types of cancer, including melanoma ( approximately 70% of cases), thyroid (30-70%), ovarian (15-30%), and colorectal cancer (5-20%).
These results reveal a novel molecular characteristic of colon tumors containing B-Raf mutations and should help in defining novel targets for cancer therapy.