Dataset Information

BRAF in malignant melanoma progression and metastasis: potentials and challenges.

ABSTRACT: Recent advances in gene sequencing have shown that activated BRAF mutations are present in more than 50% of malignant melanomas and contribute to constitutive signals in the MAPK pathway. Besides the importance of its mutations in cell proliferation, BRAF is associated with lymph node, brain and liver metastasis, along with the loss of PTEN expression and ATG5. Knowledge of this genetic alteration has led to the development of personalized and targeted therapy strategies which block different pathways driving melanoma pathogenesis. Several targeted therapy agents such as vemurafenib, dabrafenib and encorafenib have been approved by the FDA as BRAF inhibitors, as well as other immunotherapies such as anti-CTLA-4 (ipilimumab). However, one of the main challenges is acquired resistance via reactivation of MAPK via CRAF/COT overexpression. Resistance to current BRAF inhibitors is a clinical challenge and one of the strategies to overcome this phenomenon is combination treatment, with the most recently approved combination being BRAF/MEK inhibitors (dabrafenib and trametinib) and BRAF or MEK inhibitors with immunocheckpoint blockers. This review delineates the current role of BRAF in melanoma progression and metastasis. It discusses targeted therapies and resistance mechanisms to BRAF inhibitors, and illustrates strategies to overcome this mechanism with recently approved agents.

SUBMITTER: Alqathama A

PROVIDER: S-EPMC7191094 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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BRAF in malignant melanoma progression and metastasis: potentials and challenges.

Alqathama Aljawharah A

American journal of cancer research 20200401 4

Recent advances in gene sequencing have shown that activated BRAF mutations are present in more than 50% of malignant melanomas and contribute to constitutive signals in the MAPK pathway. Besides the importance of its mutations in cell proliferation, BRAF is associated with lymph node, brain and liver metastasis, along with the loss of PTEN expression and ATG5. Knowledge of this genetic alteration has led to the development of personalized and targeted therapy strategies which block different pa ...[more]

PMID: 32368388

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Project description:BackgroundData indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers. Less data are available on the clonal changes occurring during melanoma progression. We therefore wished to analyse these changes in skin melanomas in common sites of visceral metastases as compared to the primary tumor.MethodsAn autopsy cohort of 50 patients with BRAF- and NRAS-mutant cutaneous metastatic melanomas including 139 visceral metastases was analysed for mutant allele fractions (MAF), determined by pyrosequencing and corrected for tumor/normal ratio. MAF levels were also classified as high (>?40%), medium (15-40%) or low (<?15%).ResultsContrary to NRAS mutant cases, in BRAF-mutant melanomas MAFs were found to be significantly increased in visceral metastases compared to the primary due to the significantly higher levels in lung-, adrenal gland-, intestinal- and kidney metastases. The incidence of the three MAF variants in BRAF-mutant primaries was similar, whereas the high MAF cases were found to be increased in metastases. On the other hand, medium MAF levels were more common in case of NRAS-mutant tumors. Only 31.3% of BRAF mutant- and 50% of NRAS mutant cases maintained the MAF profile of the primary in metastasis. In the majority of multiple metastatic tumors, (BRAF:71.8%, NRAS:75%) metastases were relatively homogeneous regarding MAF. However, in 6/32(18.7%) of BRAF mutant cases low MAF primaries switched to high MAF in metastases. In heterogeneous BRAF mutant metastatic cases low to high or high to low MAF conversions occurred in a further 4/32(12.5%) cases in individual metastases as compared to the primary tumors. At lower frequency, in NRAS mutant tumor such changes also observed (2/12,16.7%).ConclusionWe provided evidence for the selection of BRAF-mutant melanoma cells during metastatic progression to the lung, intestine, adrenal gland and kidney. Our findings suggest that in visceral metastases of malignant melanoma BRAF- or NRAS-MAFs are rather heterogeneous and cannot be predicted from data of the primary tumor. These data may have clinical significance when using targeted therapies.

Project description:Mutations in BRAF exon 15 lead to conformational changes in its activation loops, resulting in constitutively active BRAF proteins which are implicated in the development of several human cancer types. Different BRAF inhibitors have been developed and introduced in clinical practice. Identification of BRAF mutations influences the clinical evaluation, treatment, progression and for that reason a sensitive and specific identification of BRAF mutations is on request from the clinic. Here we present the SensiScreen® FFPE BRAF qPCR Assay that uses a novel real-time PCR-based method for BRAF mutation detection based on PentaBases proprietary DNA analogue technology designed to work on standard real-time PCR instruments. The SensiScreen® FFPE BRAF qPCR Assay displays high sensitivity, specificity, fast and easy-to-use. The SensiScreen® FFPE BRAF qPCR Assay was validated on two different FFPE tumour biopsy cohorts, one cohort included malignant melanoma patients previously analyzed by the Cobas® 4800 BRAF V600 Mutation Test, and one cohort from colorectal cancer patients previously analyzed by mutant-enriched PCR and direct sequencing. All BRAF mutant malignant melanoma patients were confirmed with the SensiScreen® FFPE BRAF qPCR Assay and additional four new mutations in the malignant melanoma cohort were identified. All the previously identified BRAF mutations in the colorectal cancer patients were confirmed, and additional three new mutations not identified with direct sequencing were detected. Also, one new BRAF mutation not previously identified with ME-PCR was found. Furthermore, the SensiScreen® FFPE BRAF qPCR Assay identified the specific change in the amino acid. The SensiScreen® FFPE BRAF qPCR Assay will contribute to a more specific, time and cost saving approach to better identify and characterize mutations in patients affected by cancer, and consequently permits a better BRAF characterization that is fundamental for therapy decision.

Dataset Information

BRAF in malignant melanoma progression and metastasis: potentials and challenges.

Publications

BRAF in malignant melanoma progression and metastasis: potentials and challenges.

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