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CRCs with MMR defects are denoted as deficient MMR (dMMR) tumors. In contrast, CRCs with no MMR defects are denoted as proficient MMR (pMMR) tumors. The dMMR colorectal cancers are often poorly differentiated and frequently show proximal colon predominance, mucinous, medullary, or signet ring histologic features and increased numbers of tumor-infiltrating lymphocytes.2,3 In general, MMR deficiency may be caused either by germline mutations in one of the MMR genes with subsequent loss of the corresponding normal allele through genetic or epigenetic mechanisms, somatic mutations in the alleles, or by epigenetic inactivation of the MLH1 gene through methylation.4 The four most commonly mutated MMR genes are MLH1, PMS2, MSH2, and MSH6. In normal cells, the MLH1 protein forms a complex (heterodimer) with the PMS2 protein, while the MSH2 protein forms a complex with the MSH6 protein.5,6 When DNA mismatches occur, the MSH2/MSH6 heterodimer binds to the mismatched DNA, inducing a conformational change. The MLH1/PMS2 heterodimer binds the DNA-bound MSH2/MSH6 complex resulting in excision repair of the affected DNA.
The MLH1, PMS2, MSH2, and MSH6 proteins are clinically important MMR proteins encoded by genes that may be mutated in families with Lynch syndrome.7,8 Carriers of these mutations have a high lifetime risk of developing colorectal and other cancers due to accumulation of DNA replication errors in proliferating cells. Lynch syndrome represents 1-6% of all CRCs. These tumors result from the inheritance of a germline autosomal dominant mutation in one of the four MMR genes, with MLH1 loss occurring in the majority of these Lynch syndrome associated CRCs.5,9,10 More than 300 different mutations in the MMR family of proteins have been identified in patients with Lynch syndrome. The Lynch syndrome-associated tumor phenotype is generally characterized by immunohistochemical loss of expression in MMR proteins, particularly MLH1, PMS2, MSH2, and MSH6.10-13 MMR IHC testing has been shown to be useful in the identification of the specific MMR gene in which either a germline or a somatic alteration is most likely to be found.14
The BRAF gene is located on chromosome 7q34 and encodes a cytoplasmic serinethreonine kinase that acts downstream of the mitogen-activated protein kinase (MAPK) signaling pathway. Oncogenic mutations in the BRAF gene, all within the kinase domain, constitutively activate the MAPK signaling pathway resulting in increased cell proliferation and apoptosis resistance. The most common of all activating BRAF mutations (T1799A point mutation) results in a substitution of valine (V) to glutamic acid (E) at position 600 of the amino acid sequence and is detected in 12% of all CRC.15,16
As part of the VENTANA MMR IHC Panel, VENTANA anti-BRAF V600E (VE1) antibody aids to differentiate sporadic and probable Lynch syndrome CRC in the absence of MLH1 protein expression.17,18 In CRC, loss of MLH1 protein is frequently the result of hypermethylation of the MLH1 promoter and indicates a sporadic occurrence.19 The presence of the BRAF V600E protein is tightly linked with hypermethylation of the MLH1 promoter. As a result, a positive staining result with VENTANA anti-BRAF V600E (VE1) antibody indicates sporadic CRC.
Apart from its role in the stratification of CRC, the BRAF V600E mutation is detected in approximately 8% of all solid tumors, including 43% of melanomas, 39% of papillary thyroid carcinomas, 12% of serous ovarian carcinomas, 2% of lung cancers, and in other cancers.16 Furthermore, the BRAF V600E mutation has been recently described as a molecular marker of hairy cell leukemia.20
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Cunningham JM, Tester DJ, Thibodeau SN. Mutation detection in colorectal cancers: direct sequencing of DNA mismatch repair genes. Methods Mol Med. 2001;50:87-98.
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Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet. 2004;41(9):664-668.
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Deng G, Bell I, Crawley S, Gum J, Terdiman JP, et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10(1 Pt 1):191-195.
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",
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"Code": "Background Information"
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{
"Name": "Intended Use",
"Value": "VENTANA anti-BRAF V600E (VE1) Mouse Monoclonal Primary Antibody (VENTANA anti-BRAF V600E (VE1) antibody) is intended for the qualitative detection of BRAF V600E protein in formalin-fixed, paraffin-embedded tissue sections. VENTANA anti-BRAF V600E (VE1) antibody is ready to use on BenchMark IHC/ISH instruments with the OptiView DAB IHC Detection Kit and ancillary reagents.
VENTANA anti-BRAF V600E (VE1) antibody is part of the VENTANA MMR IHC Panel which includes VENTANA anti-MLH1 (M1) Mouse Monoclonal Primary Antibody, VENTANA anti-PMS2 (A16-4) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH2 (G219-1129) Mouse Monoclonal Primary Antibody and VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody. The VENTANA MMR IHC Panel is indicated for the detection of mismatch repair protein deficiency as a test for the identification of individuals at risk for Lynch syndrome in patients diagnosed with colorectal cancer (CRC), and, with BRAF V600E status, as an aid to differentiate between sporadic and probable Lynch syndrome CRC in the absence of MLH1 protein expression.
These products should be interpreted by a qualified pathologist in conjunction with histological examination, relevant clinical information, and proper controls.
Intended for in vitro diagnostic (IVD) use.",
"Language": "en",
"Country": "XG",
"Code": "Intended Use"
},
{
"Name": "Content",
"Value": "VENTANA anti-BRAF V600E (VE1) antibody contains sufficient reagent for 50 tests.
One 5 mL dispenser of VENTANA anti-BRAF V600E (VE1) antibody contains approximately 60 μg of mouse monoclonal antibody.
The antibody is diluted in phosphate buffer (pH 7.3) with carrier protein, Brij 35, and 0.05% ProClin 300, a preservative.
Specific antibody concentration is approximately 12 μg/mL.
VENTANA anti-BRAF V600E (VE1) antibody is a mouse monoclonal antibody produced as purified cell culture supernatant.
Refer to the appropriate VENTANA detection kit method sheet for detailed descriptions of: Principle of the Procedure, Material and Methods, Specimen Collection and Preparation for Analysis, Quality Control Procedures, Troubleshooting, Interpretation of Results, and Limitations.",
"Language": "en",
"Country": "XG",
"Code": "Content"
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"Name": "Principle",
"Value": "The VENTANA anti-BRAF V600E (VE1) antibody is a mouse monoclonal antibody (clone VE1) produced against a synthetic peptide representing the BRAF mutated amino acid sequence from amino acid 596 to 606 (GLATEKSRWSG). This mutation-specific antibody Figure 1. VENTANA anti-BRAF V600E (VE1) antibody staining of neoplastic cells in colon cancer tissue. 2023-08-16 2 / 10 1015767EN Rev F FT0700-410u exhibits a cytoplasmic staining pattern. This antibody differentiates the V600E mutation in the BRAF protein from the wild type BRAF protein and other mutated BRAF proteins.33,34 In the context of mismatch repair (MMR) IHC testing for potential Lynch syndrome, the identification of the BRAF V600E mutation in MLH1 loss cases is indicative of sporadic colorectal cancer (CRC).32
VENTANA anti-BRAF V600E (VE1) antibody binds specifically to the BRAF V600E mutant protein in formalin-fixed, paraffin-embedded (FFPE) tissue sections. The antibody can be localized using a haptenated secondary antibody followed by a multimer anti-hapten-HRP conjugate (OptiView DAB IHC Detection Kit, Cat. No. 760-700 / 06396500001). The specific antibody-enzyme complex is then visualized with a precipitating enzyme reaction product. Each step is incubated for a precise time and temperature. At the end of each incubation step, the instrument washes the sections to stop the reaction and to remove unbound material that would hinder the desired reaction in subsequent steps. It also applies ULTRA LCS (Predilute) (Cat. No. 650-210 / 05424534001) or LCS (Predilute) (Cat. No. 650-010 / 05264839001), which minimizes evaporation of the aqueous reagents from the specimen slide.",
"Language": "en",
"Country": "XG",
"Code": "Principle"
},
{
"Name": "Product Purpose",
"Value": "VENTANA anti-BRAF V600E (VE1) Mouse Monoclonal Primary Antibody (VENTANA anti-BRAF V600E (VE1) antibody) is intended for the qualitative detection of BRAF V600E protein in formalin-fixed, paraffin-embedded tissue sections. VENTANA anti-BRAF V600E (VE1) antibody is ready to use on BenchMark IHC/ISH instruments with the OptiView DAB IHC Detection Kit and ancillary reagents.
VENTANA anti-BRAF V600E (VE1) antibody is part of the VENTANA MMR IHC Panel which includes VENTANA anti-MLH1 (M1) Mouse Monoclonal Primary Antibody, VENTANA anti-PMS2 (A16-4) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH2 (G219-1129) Mouse Monoclonal Primary Antibody and VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody. The VENTANA MMR IHC Panel is indicated for the detection of mismatch repair protein deficiency as a test for the identification of individuals at risk for Lynch syndrome in patients diagnosed with colorectal cancer (CRC), and, with BRAF V600E status, as an aid to differentiate between sporadic and probable Lynch syndrome CRC in the absence of MLH1 protein expression.
These products should be interpreted by a qualified pathologist in conjunction with histological examination, relevant clinical information, and proper controls.
Intended for in vitro diagnostic (IVD) use.",
"Language": "en",
"Country": "XG",
"Code": "Product Purpose"
}
]
}
}
]
}
