Noonan Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
The BRAF gene spans 190 kb with 18 exons and encodes a serine/threonine protein kinase (B-RAF) of 766 aa, which consists of three conserved regions (CR): CR1 containing the RAS-binding domain and a cysteine-rich domain (exons 3-6), CR2b being the smallest of the conserved regions, and CR3 being the kinase domain containing a glycine-rich loop (exon 11) and an activation segment (exon 15) of the catalytic domain. Through its downstream effectors, mitogen-activated protein kinase 1 and 2 (MEK1 and MEK2), B-RAF influences cell proliferation, differentiation, motility, apoptosis, and senescence. BRAF pathogenic variants associated with classic Noonan syndrome are p.Thr241Met and p.Thr241Arg (exon 6), p.Trp531Cys (exon 13), and p.Leu597Val (exon 15), while those reported in NSML are p.Thr241Pro and p.Leu245Phe (exon 6).
Precision medicine for colorectal cancer
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
B-RAF is the strongest RAF kinase that activates MEK. Due to many missense mutations in the BRAF gene, it could be a potential target for various types of cancers. Activation of the upstream signaling pathway of RAS results in RAF activation, which induces a downstream signal transduction cascade beginning with MEK (Pearson et al., 2001). Increased MEK activity promotes activation of two kinases, namely, ERK1 and Erk2. Signaling through the ERK pathway may lead to increased growth factors and cytokines expression so that this pathway is further stimulated in an autocrine fashion (Steelman et al., 2004). Through interaction with the RB gene p27kip, ERK pathways may also increase cyclin D and E expression in the cell cycle (Steelman et al., 2004). Besides this, ERK signaling regulates cell motility, extracellular matrix remodeling, and induce the production of VEGF and other antiangiogenic factors together with inactivation of caspase and BAD. ERK also downregulates p53, which is a pivotal tumor suppressor protein. ERK could be a potential target in many cancer types. Because RAF is the only activator of ERK, drugs targeting the ERK pathway at the level of RAF may be particularly useful to control tumor development and progression. In colon cancer, mutations of B-RAF and K-RAS are often found in a mutually exclusive fashion in the same tumor. Furthermore, dominant-negative mutants of RAF can impair RAS transforming activity, confirming that inhibition of RAF is a viable therapeutic approach.
Biomarkers for the Management of Malignancies with BRAF Mutation
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Serine/threonine-protein kinase BRAF, a downstream effector of the RAS-MEK-ERK signaling pathway, has emerged as an important biological marker for diagnosis, prognostication, and therapeutic selection for patients with cancer. BRAF is a key driver oncogene that is frequently mutated in a diverse range of human cancers [1]. Targeted inactivation of BRAF by pharmacologic inhibitors is one of the most successful therapeutic interventions for cancers [2, 3]. Consequently, BRAF gene mutation testing has emerged as an important tool for diagnosis, prognosis, selection of treatment, and predicting patient outcome in response to targeted therapy for multiple cancer types. While responses to BRAF targeted therapies are common, therapy-induced tumor resistance occurs [3]. Emerging biomarkers assessing BRAF and the pathway focus on identifying actionable drivers and determinants of resistance [4].
Deciphering the genotype and phenotype of hairy cell leukemia: clues for diagnosis and treatment
Published in Expert Review of Clinical Immunology, 2019
Margot C.E. Polderdijk, Michiel Heron, Saskia Kuipers, Ger T. Rijkers
The BRAF gene is located on chromosome 7q34, and codes for the B-Raf protein. This protein, like other members of the Raf kinase family, has a function in signal transduction, specifically in a pathway affecting cell division, differentiation and secretion: the MAP kinase/ERKs signaling pathway (see Figure 3). B-Raf consists of 766 amino acids, from which three conserved regions can be identified, connected by a GTP-binding domain and a serine-rich hinge region. Various mutations in the BRAF gene have been linked to the development of certain types of cancer, for example colorectal cancer, thyroid cancer, melanoma, and hairy cell leukemia. Figure 4 shows the distribution of the currently published mutations over the gene. In BRAF, there are clearly several hotspots, which is different compared to the BRCA1 gene (Figure 5). Overall, BRAF mutations are found in 8% of human cancers [49]. Because of the many different signaling pathways in which BRAF participates, this finding is not very surprising. However, while the role of BRAF in pathogenesis of cancer might seem self-evident, the clinical implications across different forms of cancer types differ. Furthermore, determination of the exact role of BRAF is complicated when other, simultaneous, oncogenic mutations are involved.
BRAF testing in a South African cohort of MLH1 deficient endometrial carcinomas: lessons learnt
Published in Southern African Journal of Gynaecological Oncology, 2021
BRAF is a subtype of RAF protein that has serine-threonine kinase activity, and forms part of the RAS/RAF/MAP/ERK pathway that culminates in cell proliferation.1 Activity of RAF is usually under control of RAS. Constitutive activation of the RAS/RAF/MAP/ERK pathway occurs due to mutations in BRAF V600E, resulting in carcinogenesis. Studies have shown that BRAF V600E codon mutations result in ten times the tyrosine kinase activity in contrast to wild-type BRAF.2 Tyrosine kinases are involved in cellular communication and assist in the regulation of cell growth and differentiation of cells. Thus, tyrosine kinase dysregulation culminates in an assortment of disorders, in particular neoplasia.3 The role of BRAF mutations in tumours such as malignant melanomas and colorectal carcinomas is well established and such mutations are identified in up to half of colonic carcinomas.4 The presence of MLH1 promoter hypermethylation, as well as mutations in BRAF V600E, suggests sporadic occurrence of a colorectal neoplasm.5
Targeting the EGFR signaling pathway in cancer therapy: What’s new in 2023?
Published in Expert Opinion on Therapeutic Targets, 2023
Sushanta Halder, Soumi Basu, Shobhit P. Lall, Apar K. Ganti, Surinder K. Batra, Parthasarathy Seshacharyulu
In the future, multiple molecular agents can be combined to obtain superior tumor cell killing and extend the survival of cancer patients. For example, NSCLC tumors found a way to tackle osimertinib by developing acquired resistance against it, especially via B-Raf proto-oncogene (BRAF) mutation, which is a downstream signaling molecule of EGFR. BRAF is a component of RAS/MAPK signaling, which engages in cell growth and transformation. BRAF V600 involves the exchange of valine to glutamate at 600th residue on exon 15, which is a constitutive active BRAF mutation and further leads to tumor cell growth, invasion, and reduction of apoptosis. In an anecdotal report of a patient who developed a BRAF V600 mutation, a triple therapy involving dabrafenib, trametinib, and osimertinib targeting EGFR/BRAF/MEK pathway showed clinical improvement and partial tumor suppression [161].
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