Beyond the BRAF ^{V 600E} hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients

Abstract

BRAF gene mutations can be found in approximately 50% of melanomas, but the most common BRAF mutation leads to substitution at residue 600 of the protein, from valine to glutamic acid. BRAF occurs in up to 95% of all melanoma cases and can be successfully blocked by using a combination of BRAF- and MEK inhibitors. The wider availability of next-generation sequencing is revealing more non-V600 BRAF mutations, and the clinical implications of these mutations are widely unknown. In this review, we will discuss the biology of the MAPK pathway and the different types of BRAF mutations as well as their effect on MEK activation. Current literature will be reviewed including in vitro data, case reports and case series.

Improving the Design of Synthetic Oligonucleotide Probes by Fluorescence Melting Assay

“…Furthermore, BRAF V600E is the most predominant mutation (up to 90 % of cases) of BRAF mutations in melanoma. Moreover, BRAF V600E‐mutated melanoma tends to have more aggressive biological behaviour than BRAF wild‐type melanoma . The transversion of T into A requires sensitive T m studies to evaluate the mutation or the design of specific nucleic acid detection probes for diagnostic proposes …”

“…Therefore, we performed a similar series of experiments for a different duplex. We extended the oligonucleotide test system and designed a 21‐mer antisense strand that targets the RNA of the human oncogene BRAF . This genetic mutation is mediated by single‐nucleotide polymorphism (T→A) at gene position 1799 in human DNA that facilitates substitution of valine to glutamic acid at residue 600 of the serine/threonine‐protein kinase B‐Raf.…”

Cutaneous melanoma: From pathogenesis to therapy (Review)

“…The catalytic domain is also responsible for maintaining the protein in its inactive conformation, through a hydrophobic interaction between the 'so-called' glycine-rich loop and the activation segment, making it inaccessible for ATP binding ( 59 ). In the BRAF V600E mutation, hydrophobic valine is replaced by polar, hydrophilic glutamic acid, resulting in an abnormal flip of the catalytic domain that generates a constitutive active conformation with a kinase activity 500-fold higher than wild-type BRAF kinase ( 60 , 61 ). Most of the non-V600E BRAF mutations act similarly through the alteration of glycine-rich loop and activation segment interaction, thus increasing BRAF kinase activity ( 61 ).…”

“…In the BRAF V600E mutation, hydrophobic valine is replaced by polar, hydrophilic glutamic acid, resulting in an abnormal flip of the catalytic domain that generates a constitutive active conformation with a kinase activity 500-fold higher than wild-type BRAF kinase ( 60 , 61 ). Most of the non-V600E BRAF mutations act similarly through the alteration of glycine-rich loop and activation segment interaction, thus increasing BRAF kinase activity ( 61 ).…”

Function and Clinical Implications of Long Non-Coding RNAs in Melanoma

“…Usually Rat sarcoma (RAS) activates Rapidly Accelerated Fibrosarcoma (RAF), which propagates down-stream signaling through MAPK/ERK Kinase (MEK) to extracellular signal-regulated kinase (ERK). When a high-kinase activity mutation in BRAF occurs, it can independently activate the MAPK pathway and in fact BRAF V600E has a ~500-fold increased activity compared to BRAF wt [11]. …”