A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Ratner, Nancy; Miller, Shyra J.

doi:10.1038/nrc3911

Cited by 372 publications

(392 citation statements)

References 199 publications

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“…NF1 encodes Neurofibromin 1, a Ras-GAP, that switches the Ras protein from its active GTP-bound state into its inactive GDPbound state, thereby turning off MAPK signalling promoted proliferation 45 . Inactivating NF1 mutations are found at high frequency not only in Neurofibromatosis 1 46 but also in a variety of cancers like melanoma 47,48 , glioblastoma 49,50 and ovarian cancer 51 .…”

Section: Spred2 Sensitises Cells Through Nf1mentioning

confidence: 99%

Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens

Boettcher

Tian

Blau

et al. 2017

Preprint

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SummaryGenetic interaction studies are a powerful approach to identify functional interactions between genes. This approach can reveal networks of regulatory hubs and connect uncharacterised genes to well-studied pathways. However, this approach has previously been limited to simple gene inactivation studies. Here, we present an orthogonal CRISPR/Cas-mediated genetic interaction approach that allows the systematic activation of one gene while simultaneously knocking out a second gene in the same cell. We have developed this concept into a quantitative and scalable combinatorial screening platform that allows the parallel interrogation of hundreds of thousands of genetic interactions. We demonstrate that the established platform works robustly to uncover genetic interactions in human cancer cells and to interpret the direction of the flow of genetic information.peer-reviewed)

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Section: Spred2 Sensitises Cells Through Nf1mentioning

confidence: 99%

Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens

Boettcher

Tian

Blau

et al. 2017

Preprint

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“…Its clinical diagnosis is based on the presence of café-au-lait maculae , axillar or inguinal freckling, neurofi bromas and plexiform neurofi bromas, iris Lisch nodules, osseous dysplasia, and optic pathway glioma . In addition, individuals have "Noonan-like" faces, mild neurocognitive impairment and a predisposition to developing certain malignancies, such as central nervous system tumors ( gliomas and astrocytomas ), neurofi brosarcomas, and juvenile myelomonocytic leukemia (JMML) that result in reduced life span [ 6 ].…”

Section: Types Of Mouse Modelsmentioning

confidence: 99%

Modeling RASopathies with Genetically Modified Mouse Models

Hernández-Porras

Guerra

2016

Methods in Molecular Biology

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The RAS/MAPK signaling pathway plays key roles in development, cell survival and proliferation, as well as in cancer pathogenesis. Molecular genetic studies have identified a group of developmental syndromes, the RASopathies, caused by germ line mutations in this pathway. The syndromes included within this classification are neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS, NF1-like syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and hereditary gingival fibromatosis (HGF) type 1. Although these syndromes present specific molecular alterations, they are characterized by a large spectrum of functional and morphological abnormalities, which include heart defects, short stature, neurocognitive impairment, craniofacial malformations, and, in some cases, cancer predisposition. The development of genetically modified animals, such as mice (Mus musculus), flies (Drosophila melanogaster), and zebrafish (Danio rerio), has been instrumental in elucidating the molecular and cellular bases of these syndromes. Moreover, these models can also be used to determine tumor predisposition, the impact of different genetic backgrounds on the variable phenotypes found among the patients and to evaluate preventative and therapeutic strategies. Here, we review a wide range of genetically modified mouse models used in the study of RASopathies and the potential application of novel technologies, which hopefully will help us resolve open questions in the field.

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“…The diagnosis of NF1 is based on National Institutes of Health clinical consensus criteria [2,3], with the main clinical features including multiple café-au-lait macules, axillary freckling, Lisch nodules, optic pathway gliomas, peripheral nerve sheath tumors, multiple forms of cognitive dysfunction, and a higher risk of cancers such as pheochromocytoma and breast cancer in young women. NF1 is caused by various DNA alterations, including point mutations, deletions, insertions, microdeletions, and splicing mutations of the NF1 tumor suppressor gene at 17q11.2, which encodes the GTPase activating protein neurofibromin that catalyzes the inactivation of Ras by accelerating guanosine triphosphate hydrolysis to guanosine diphosphate [4,5]. In affected individuals, truncation or loss of neurofibromin results in activated Ras with subsequent activation of the Raf-mitogen-activated protein kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade.…”

Section: Introduction To Neurofibromatosismentioning

confidence: 99%

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

2017

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The RASopathy neurofibromatosis 1 is an autosomal dominant hereditary cancer syndrome that represents a major risk for the development of malignancies, particularly malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are unique sarcomas that originate from the peripheral nerve and represent the only primary cancer of the peripheral nervous system. To date, surgery is the only treatment modality proven to have survival benefit for MPNSTs and even when maximal surgery is feasible, these tumors are rarely curable, despite the use of chemotherapy and radiation. In this review, we discuss the current state-of-the-art treatments for MPNSTs, latest therapeutic developments, and critical aspects of the underlying molecular and pathophysiology that appear promising for therapeutic developments in the future. In particular, we discuss the specific elements of cancer in the peripheral nerve and how that may impel development of unique therapies for this form of sarcoma.

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A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Cited by 372 publications

References 199 publications

Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens

Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens

Modeling RASopathies with Genetically Modified Mouse Models

Cancer of the Peripheral Nerve in Neurofibromatosis Type 1

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