Utilization of a MAB for BRAFV600E detection in papillary thyroid carcinoma

Bullock, Martyn; OʼNeill, Christine; Chou, Angela; Clarkson, Adele; Dodds, Tristan; Toon, Christopher W.; Sywak, Mark; Sidhu, Stanley; Delbridge, Leigh; Robinson, Bruce G.; Learoyd, Diana; Capper, David; Deimling, Andreas von; Clifton‐Bligh, Roderick; Gill, Anthony J.

doi:10.1530/erc-12-0239

Cited by 68 publications

(71 citation statements)

References 14 publications

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“…In the TCGA dataset, 86% of classic PTCs with BRAF V600E had more than 25% of the mutated alleles. In studies using a mutation-specific antibody against the BRAF V600E protein, the immunostaining pattern was homogenous in most PTCs, supporting the BRAF mutation as a clonal event (Bullock et al 2012, Koperek et al 2012, Ghossein et al 2013. Recently, de Biase et al (2014) have found the heterogeneous distribution of BRAF V600E within the PTC using both immunohistochemistry and quantitative DNA analytical methods.…”

Section: Discussionmentioning

confidence: 88%

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Kim¹,

Bae²,

Lim³

et al. 2014

Endocrine-Related Cancer

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The BRAF V600E mutation is the most common genetic alteration in thyroid cancer. However, its clinicopathological significance and clonal mutation frequency remain unclear. To clarify the inconsistent results, we investigated the association between the allelic frequency of BRAF V600E and the clinicopathological features of classic papillary thyroid carcinoma (PTC). Tumour tissues from two independent sets of patients with classic PTC were manually microdissected and analysed for the presence or absence of the BRAF mutation and the mutant allelic frequency using quantitative pyrosequencing. For external validation, the Cancer Genome Atlas (TCGA) data were analysed. The BRAF V600E mutation was found in 264 (82.2%) out of 321 classic PTCs in the training set. The presence of BRAF V600E was only associated with extrathyroidal extension and the absence of thyroiditis. In BRAF V600E-positive tumours, the mutant allelic frequency varied from 8 to 41% of the total BRAF alleles (median, 20%) and directly correlated with tumour size and the number of metastatic lymph nodes. Lymph node metastases were more frequent in PTCs with a high (R20%) abundance of mutant alleles than in those with a low abundance of mutant alleles (PZ0.010). These results were reinforced by validation dataset (nZ348) analysis but were not reproduced in the TCGA dataset. In a population with prevalent BRAF mutations, quantitative analysis of the BRAF mutation could provide additional information regarding tumour behaviour, which is not reflected by qualitative analysis. Nonetheless, prospective studies are needed before the mutated allele percentage can be considered as a prognostic factor.

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Section: Discussionmentioning

confidence: 88%

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Kim¹,

Bae²,

Lim³

et al. 2014

Endocrine-Related Cancer

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“…33,34 Implementation of VE1 immunohistochemistry for the prediction of a BRAF V600E mutation has been investigated by various groups and for various types of cancer. [15][16][17][18][19][20][21][23][24][25] VE1 immunohistochemistry has the advantage of being rapid and relatively inexpensive, while the sensitivity and specificity are comparable to DNA-based methods. For pathologists, an additional well-appreciated advantage is the in situ mutation detection that provides information on the mutated cell population, as well as an additional visual sample verification that a faceless DNA sample does not offer.…”

Section: Discussionmentioning

confidence: 99%

“…2 In this study, we investigated a large collection of biliary tract cancers for BRAF V600E mutations using a novel mutation-specific antibody (clone VE1) that specifically binds to BRAF V600E-mutated protein that is in general located in the cytoplasm. VE1 immunohistochemistry has proven to be highly sensitive and specific for various tumor types, including melanoma, [15][16][17][18][19] thyroid carcinoma, 20,21 colorectal carcinoma, 22,23 ganglioglioma, 24 and hairy cell leukemia, 25 among others.…”

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confidence: 99%

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

et al. 2014

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BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n ¼ 377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatic cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.

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“…Two recent studies investigating the performance of VE1 in melanoma and papillary thyroid carcinoma both observed increased sensitivity for BRAF V600E mutation detection compared to Sanger sequencing. 31,32 For papillary thyroid carcinoma, VE1 immunohistochemistry was proposed as a new standard method of BRAF mutation detection, largely because of increased sensitivity compared to sequencing. 31 For melanoma, sequential analysis of VE1 immunohistochemistry and pyrosequencing was proposed as the most robust assay to identify BRAF mutations.…”

Section: Cancer Geneticsmentioning

confidence: 99%

“…31,32 For papillary thyroid carcinoma, VE1 immunohistochemistry was proposed as a new standard method of BRAF mutation detection, largely because of increased sensitivity compared to sequencing. 31 For melanoma, sequential analysis of VE1 immunohistochemistry and pyrosequencing was proposed as the most robust assay to identify BRAF mutations. 32 Reminiscent of our single discordant tumor, among the papillary thyroid carcinoma series three lesions staining positive for VE1 could not be confirmed by sequencing, not even by massive parallel sequencing.…”

Section: Cancer Geneticsmentioning

confidence: 99%

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Capper

Voigt

Bozukova

et al. 2013

Intl Journal of Cancer

101

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The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1-and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n 5 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.Lynch syndrome, which represents one of the most frequent autosomal dominantly inherited cancer syndromes, is caused by germline mutations affecting DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2, followed by MSH6 and PMS2.

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Utilization of a MAB for BRAFV600E detection in papillary thyroid carcinoma

Cited by 68 publications

References 14 publications

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

Quantification of BRAF V600E alleles predicts papillary thyroid cancer progression

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

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