BRAF<sup>V600E</sup>Protein Expression in Primary Cutaneous Malignant Melanomas and Paired Metastases

Eriksson, Hanna; Zebary, Abdlsattar; Vassilaki, Ismini; Omholt, Katarina; Ghaderi, Mehran; Hansson, Johan

doi:10.1001/jamadermatol.2014.3689

Cited by 28 publications

(32 citation statements)

References 33 publications

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“…Even though the initial belief was that the BRAF V600E mutation is acquired early in melanoma pathogenesis, some studies have suggested the existence of BRAF V600E heterogeneity in melanoma tumours, and they have described discordance in the range of 13.5–44% with different molecular methods. Most previous studies reporting intertumour heterogeneity have used molecular PCR‐based techniques for BRAF V600E testing.…”

Section: Discussionmentioning

confidence: 96%

“…As IHC analysis is an in‐situ method, it is also able to detect intratumour and intertumour heterogeneity in the tissue, in contrast to molecular tests. The presence of intertumour and intratumour heterogeneity has been a subject of great debate over the past couple of years, and recent studies have demonstrated the presence of both BRAF V600E heterogeneity and homogeneity in melanoma tumours . The presence of intertumour and intratumour heterogeneity of the BRAF V600E mutation in melanoma might be an intrinsic mechanism of resistance to BRAF inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

et al. 2018

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IHC analysis can be safely used as a BRAF pretreatment screening tool, and no additional test is needed when staining is positive. However, if stains are negative, additional tests are essential for detection of other BRAF mutations. We suggest that using primary melanoma tissues is just as safe as using metastatic tissue for detection of BRAF V600E, as BRAF intertumour heterogeneity is extremely rare. In addition, the time between diagnosis of the primary tumour and diagnosis of the corresponding metastasis seems not to increase the risk of intertumour heterogeneity.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

et al. 2018

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“…It is noteworthy that in previous work on BRAF status discordance between primary and metastatic melanoma, the pooled rate of discordance was lower in studies using IHC to detect mutant protein, compared with those using DNA‐based approaches . Across seven studies using the VE1 anti‐V600E BRAF antibody, the mean discordance was 5.6% . By contrast, the mean discordance was 14% in DNA‐based studies .…”

Section: Introductionmentioning

confidence: 84%

“…The largest study to use IHC to compare BRAF status between primary melanomas and their metastases was Boursault et al, which included 88 patients and reported discordance in 4.5% . While rates of discordance on IHC as high as 27.5% have been reported, no study including more than 50 patients has shown discordance in more than 5% of cases . The characteristics of previous studies addressing this issue by means of IHC are summarized in Table .…”

Section: Discussionmentioning

confidence: 99%

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High concordance of BRAF mutational status in matched primary and metastatic melanoma

et al. 2018

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Background Techniques for the accurate identification of activating mutations of BRAF in metastatic melanoma are of great clinical importance, due to the availability of targeted therapies for these tumors. There is uncertainty regarding the frequency with which BRAF status differs between primary and metastatic sites. Methods Between 2011 and 2016, 219 melanoma cases underwent BRAF testing in our institution. In 53 of these cases, paired primary and metastatic specimens were available for polymerase chain reaction (PCR) and immunohistochemical evaluation. Results Fifty‐two out of 53 cases (98%) showed concordant BRAF status between primary and metastatic site by immunohistochemistry (IHC). In one case, a metastasis and its matched primary were positive by IHC, but the metastasis was negative on PCR. On further investigation, PCR was positive in the primary, and repeat PCR in the metastasis was positive, following macrodissection. Conclusions Our results suggest that discordance of BRAF mutational status between primaries and metastases is a rare occurrence. In one case, IHC provided strong evidence that initial PCR testing had provided a false‐negative result due to low tumor volume. Thus, in cases where tissue is difficult to obtain from a metastasis or unavailable, the primary tumor can be used with confidence.

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Genetic progression of malignant melanoma

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et al. 2016

Cancer Metastasis Rev

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Malignant melanoma of the skin is the most aggressive human cancer given that a primary tumor a few millimeters in diameter frequently has full metastatic competence. In view of that, revealing the genetic background of this potential may also help to better understand tumor dissemination in general. Genomic analyses have established the molecular classification of melanoma based on the most frequent driver oncogenic mutations (BRAF, NRAS, KIT) and have also revealed a long list of rare events, including mutations and amplifications as well as genetic microheterogeneity. At the moment, it is unclear whether any of these rare events have role in the metastasis initiation process since the major drivers do not have such a role. During lymphatic and hematogenous dissemination, the clonal selection process is evidently reflected by differences in oncogenic drivers in the metastases versus the primary tumor. Clonal selection is also evident during lymphatic progression, though the genetic background of this immunoselection is less clear. Genomic analyses of metastases identified further genetic alterations, some of which may correspond to metastasis maintenance genes. The natural genetic progression of melanoma can be modified by targeted (BRAF or MEK inhibitor) or immunotherapies. Some of the rare events in primary tumors may result in primary resistance, while further new genetic lesions develop during the acquired resistance to both targeted and immunotherapies. Only a few genetic lesions of the primary tumor are constant during natural or therapy-modulated progression. EGFR4 and NMDAR2 mutations, MITF and MET amplifications and PTEN loss can be considered as metastasis drivers. Furthermore, BRAF and MITF amplifications as well as PTEN loss are also responsible for resistance to targeted therapies, whereas NRAS mutation is the only founder genetic lesion showing any association with sensitivity to immunotherapies. Unfortunately, there are hardly any data on the possible organ-specific metastatic drivers in melanoma. These observations suggest that clinical management of melanoma patients must rely on the genetic analysis of the metastatic lesions to be able to monitor progression-associated changes and to personalize therapies.

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BRAF^V600EProtein Expression in Primary Cutaneous Malignant Melanomas and Paired Metastases

Cited by 28 publications

References 33 publications

Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

High concordance of BRAF mutational status in matched primary and metastatic melanoma

Genetic progression of malignant melanoma

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BRAFV600EProtein Expression in Primary Cutaneous Malignant Melanomas and Paired Metastases

Cited by 28 publications

References 33 publications

Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

High concordance of BRAF mutational status in matched primary and metastatic melanoma

Genetic progression of malignant melanoma

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BRAF^V600EProtein Expression in Primary Cutaneous Malignant Melanomas and Paired Metastases