Abstract:Pilocytic astrocytoma (PA) is one of the most common brain cancers among children and activation of the Mitogen-Activated Protein Kinase (MAPK) pathway is considered the hallmark. In the majority of cases, oncogenic BRAF fusions or BRAF V600E mutations are observed, while RAF1 or NF1 alterations are more rarely found. However, in some cases, no apparent cancer driver events can be identified. Here, we describe a novel fusion between the transcription factor nuclear factor 1A (NFIA) and Raf-1 proto-oncogene (RA… Show more
“…Consistently, NFIs as fusion proteins appear to increase the activity of their respective fusion partners' downstream signalling pathways, but do not appear to effect NFI regulatory target gene expression . Fusion proteins have been reported with transcription factors (NFIB‐MYB), chromatin modifying complexes (NFIA‐CBFA2T3) and kinases (NFIA‐RAF1) and usually contain only a partial form of NFI . Studies discussed previously in this review highlight NFIs role in forming chromatin domain barrier/boundaries that block the propagation of silencing signals emanating from heterochromatic silent regions within the telomere .…”
Section: Epigenetic Mechanisms Of Nfis In Cancermentioning
Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell-like state. This stem cell-like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell-like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell-intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression.
“…Consistently, NFIs as fusion proteins appear to increase the activity of their respective fusion partners' downstream signalling pathways, but do not appear to effect NFI regulatory target gene expression . Fusion proteins have been reported with transcription factors (NFIB‐MYB), chromatin modifying complexes (NFIA‐CBFA2T3) and kinases (NFIA‐RAF1) and usually contain only a partial form of NFI . Studies discussed previously in this review highlight NFIs role in forming chromatin domain barrier/boundaries that block the propagation of silencing signals emanating from heterochromatic silent regions within the telomere .…”
Section: Epigenetic Mechanisms Of Nfis In Cancermentioning
Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell-like state. This stem cell-like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell-like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell-intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression.
“…RAF1 mutations have mostly been found in large bowel and skin cancer, but only once in glioma (COSMIC database). However, it is well established that rearrangements of RAF1 with for example SRGAP3 , NFIA , ATG7 , or QKI most likely lead to hyperactivation of RAF1 and, therefore, play a role as somatic events in pilocytic and low grade astrocytomas, or low grade gliomas (Jones et al, ; Phillips et al, ; Yde et al, ; Zhang et al, ). Development of two independent childhood tumors in patient 1 is very unusual for NS, but as a single observation it is still insufficient to support the hypothesis that the c.1082G>C/p.…”
Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.
“…RAF1 fusions are observed in some cancers, typically resulting (much like BRAF fusions) in an aberrant gene product fusing the C-terminal CRAF kinase domain to an N-terminal fusion partner with a dimerization domain that leads to RAS-independent dimerization and activation of CRAF kinase activity. These fusions are found in low-grade pediatric gliomas, prostate cancer, melanoma, and pancreatic cancer (26,(31)(32)(33).…”
Section: Non-braf Alterations In Raf Genesmentioning
The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer. Although RAS mutations are the most frequent MAPK alterations, less frequent alterations in downstream components of the pathway, including the RAF and MEK genes, offer promising therapeutic opportunities. In addition to BRAF V600 mutations, for which several approved therapeutic regimens exist, other alterations in the RAF and MEK genes may provide more rare, but tractable, targets. However, recent studies have illustrated the complexity of MAPK signaling and highlighted that distinct alterations in these genes may have strikingly different properties. Understanding the unique functional characteristics of specifi c RAF and MEK alterations, reviewed herein, will be critical for developing effective therapeutic approaches for these targets.Signifi cance: Alterations in the RAF and MEK genes represent promising therapeutic targets in multiple cancer types. However, given the unique and complex signaling biology of the MAPK pathway, the diverse array of RAF and MEK alterations observed in cancer can possess distinct functional characteristics. As outlined in this review, understanding the key functional properties of different RAF and MEK alterations is fundamental to selecting the optimal therapeutic approach.Research. on July 5, 2020.
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