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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 immunohisto-chemical loss of expression in MMR proteins, particularly MLH1, PMS2, MSH2, and MSH6.10,11,12,13 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 As part of the VENTANA MMR IHC Panel, VENTANA anti-BRAF V600E (VE1) Mouse Monoclonal Primary Antibody (VENTANA anti-BRAF V600E (VE1) antibody) aids to differentiate sporadic and probable Lynch syndrome CRC in the absence of MLH1 protein expression.15,16 In CRC, loss of MLH1 protein is frequently the result of hypermethylation of the MLH1 promoter and indicates a sporadic occurrence.17 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.
1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. 2. Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011;135(10):1269-1277. 3. Wright CL, Stewart ID. Histopathology and mismatch repair status of 458 consecutive colorectal carcinomas. Am J Surg Pathol. 2003;27(11):1393-1406. 4. Tiwari AK, Roy HK, Lynch HT. Lynch syndrome in the 21st century: clinical perspectives. QJM. 2016;109(3):151-158. v5. Buza N, Ziai J, Hui P. Mismatch repair deficiency testing in clinical practice. Expert Rev Mol Diagn. 2016;16(5):591-604. 6. Silva FCC, Torrezan GT, Ferreira JRO, Oliveira LP, Begnami M, et al. Germline Mutations in MLH1 Leading to Isolated Loss of PMS2 Expression in Lynch Syndrome: Implications for Diagnostics in the Clinic. Am J Surg Pathol. 2017;41(6):861-864. 7. Boyer JC, Umar A, Risinger JI, Lipford JR, Kane M, et al. Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res. 1995;55(24):6063-6070. 8. Lawes DA, Pearson T, Sengupta S, Boulos PB. The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers. Br J Cancer. 2005;93(4):472-477. 9. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348(10):919-932. 10. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174-1179. 11. Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer. 1996;78(6):1149-1167. 12. Caldes T, Godino J, Sanchez A, Corbacho C, De la Hoya M, et al. Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. Oncol Rep. 2004;12(3):621-629. 13. Shia J, Klimstra DS, Nafa K, Offit K, Guillem JG, et al. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol. 2005;29(1):96-104. 14. 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. 15. 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. 16. Jin M, Hampel H, Zhou X, Schunemann L, Yearsley M, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Clin Pathol. 2013;140(2):177-183. 17. 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.",
"Language": "en",
"Country": "XG",
"Code": "Background Information"
},
{
"Name": "Intended Use",
"Value": "VENTANA anti-PMS2 (A16-4) Mouse Monoclonal Primary Antibody (VENTANA anti-PMS2 (A16-4) antibody) is intended for the qualitative detection of PMS2 protein in formalin- fixed, paraffin-embedded tissue sections. VENTANA anti-PMS2 (A16-4) antibody is ready to use on BenchMark ULTRA, XT, and GX instruments with the OptiView DAB IHC Detection Kit, OptiView Amplification Kit, and ancillary reagents.
VENTANA anti-PMS2 (A16-4) antibody is part of the VENTANA MMR IHC Panel which includes VENTANA anti- MLH1 (M1) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH2 (G219- 1129) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody and VENTANA anti-BRAF V600E (VE1) Mouse 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-PMS2 (A16-4) antibody contains sufficient reagent for 50 tests.
One 5 mL dispenser of VENTANA anti-PMS2 (A16-4) antibody contains approximately 5 μg of a mouse monoclonal antibody. The antibody is diluted in PBS containing carrier protein and 0.05% ProClin 300, a preservative. Specific antibody concentration is approximately 1 μg/mL. There is no known non-specific antibody reactivity observed in this product. VENTANA anti-PMS2 (A16-4) antibody is a mouse monoclonal antibody produced as 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"
},
{
"Name": "Principle",
"Value": "VENTANA anti-PMS2 (A16-4) antibody is a mouse monoclonal antibody produced against a recombinant PMS2 protein. VENTANA anti-PMS2 (A16-4) antibody binds to PMS2 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) and the OptiView Amplification Kit (Cat. No. 760-099 / 06396518001 (50 test) or 860-099 / 06718663001 (250 test)). The specific antibody-enzyme complex is then visualized 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-PMS2 (A16-4) Mouse Monoclonal Primary Antibody (VENTANA anti-PMS2 (A16-4) antibody) is intended for the qualitative detection of PMS2 protein in formalin- fixed, paraffin-embedded tissue sections. VENTANA anti-PMS2 (A16-4) antibody is ready to use on BenchMark ULTRA, XT, and GX instruments with the OptiView DAB IHC Detection Kit, OptiView Amplification Kit, and ancillary reagents.
VENTANA anti-PMS2 (A16-4) antibody is part of the VENTANA MMR IHC Panel which includes VENTANA anti- MLH1 (M1) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH2 (G219- 1129) Mouse Monoclonal Primary Antibody, VENTANA anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody and VENTANA anti-BRAF V600E (VE1) Mouse 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"
}
]
}
}
]
}
