BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry

Abstract

The B-Raf proto-oncogene (BRAF) encodes a cytoplasmic serine/threonine kinase with a key role in regulating the mitogen-activated protein kinase signal transduction pathway. An activating missense mutation in codon 600 of exon 15 (V600E) of BRAF gene has been identified in multiple neoplasms including melanoma, colorectal carcinoma, papillary thyroid carcinoma, hairy cell leukemia, and Langerhans cell histiocytosis. Patients with BRAF V600E-mutated melanoma respond to FDA-approved BRAF inhibitors. In addition, subsets of other BRAF V600E-mutated tumors may also benefit from BRAF inhibitor therapy. Currently, clinical laboratories typically use molecular-based methods for mutation analysis. However, recently a BRAF V600E mutation-specific antibody has become available as a cost-effective alternative method to DNA-based molecular testing. We analyzed multiple tumor types including melanoma, colorectal carcinoma, papillary thyroid cancer, hairy cell leukemia, and Langerhans cell histiocytosis using both DNA-based sequencing and the BRAF V600E mutation-specific antibody. Our results show a high degree of concordance between the 2 methods. However, the high concordance seems to be limited only to the V600E mutation since variant V600 mutations are missed by V600E mutation-specific immunohistochemistry.

The Role of Snail-1 in Thyroid Cancer—What We Know So Far

“…The B-Raf proto-oncogene (BRAF) gene is located on chromosome 7q34 and is responsible for encoding a cytoplasmic protein kinase—a part of the mitogen-activated protein kinase pathway (MAPK). BRAF oncogenic mutations lead to a permanent activation of the MAPK signaling, which in turn results in increased cell proliferation, apoptosis resistance and uncontrolled tumour growth [ 43 ]. The substitution of valine (V) by glutamate (E) at position 600 of the B-Raf protein, accounts for approximately 90% of all BRAF mutations and is designated as V600E [ 44 ].…”

Population-based Screening for BRAFV600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis

“…Between 8% and 10% of colorectal cancers have a BRAF V600E -activating mutation (2), which leads to RASindependent MAPK pathway activation, tumor cell proliferation, and survival. BRAF V600E has been well-studied in other neoplasms (3), most commonly in melanoma, for which targeted therapies are available (4). In colorectal cancer, BRAF V600E -targeted therapies have been less successful (5).…”

On the Shoulders of a Giant: Contributions of Thomas Grogan, MD to Hematopathology

“…A cost-effective alternative to molecular testing comes from mutation-specific antibodies that can facilitate the detection of a specific mutation by immunohistochemistry. One such example is BRAF V600E, a mutation in the BRAF-encoded serine/threonine kinase that is found in a variety of malignancies including melanoma, colorectal carcinoma, thyroid carcinoma, hairy cell leukemia, and Langerhans cell histiocytosis among other neoplasms [59,60]. Comparative DNA sequence analysis along with BRAF V600E-specific immunohistochemistry showed a high degree of concordance and supports the use of immunohistochemistry for the detection of this mutation in relevant cancer types [60].…”

“…One such example is BRAF V600E, a mutation in the BRAF-encoded serine/threonine kinase that is found in a variety of malignancies including melanoma, colorectal carcinoma, thyroid carcinoma, hairy cell leukemia, and Langerhans cell histiocytosis among other neoplasms [59,60]. Comparative DNA sequence analysis along with BRAF V600E-specific immunohistochemistry showed a high degree of concordance and supports the use of immunohistochemistry for the detection of this mutation in relevant cancer types [60]. In addition, antibodies that detect epigenetic modifications that are associated with hyper-or hypomethylation such as the H3K27me3 antibody allows the detection of histone H3 methylation at K27 in tissue biopsies.…”