Importance:Neurofibromatosis type 1 (NF1) is a multisystem, tumor predisposition syndrome in which vascular manifestations, including cutaneous lesions, remain poorly characterized. Cherry angiomas (CAs) have been sporadically reported in NF1, but their prevalence and biological basis are unknown. Objective:To assess the association between NF1 and CAs and define the histopathologic, cellular, and genetic mechanisms underlying NF1-associated CAs. Design, Setting, and Participants:This prospective, comparative, cross-sectional epidemiological study was conducted from October 2020 to March 2021 at a French national referral center for neurofibromatoses within the dermatology department at Henri-Mondor University Hospital, Créteil, France. It was followed by integrated histopathologic, genomic, and cell-specific molecular analyses. The epidemiological analysis included individuals 15 years or older with confirmed NF1 and controls without NF1. Pathophysiological analyses were conducted on CAs from individuals with NF1 and healthy volunteers following written consent. Data were analyzed in 2022. Main Outcomes and Measures:Outcomes included the prevalence of CAs; age-adjusted and sex-adjusted odds ratios; histopathologic features; detection of somatic NF1 second-hit variants; identification of co-occurring oncogenic variants; localization of NF1 loss within vascular cell populations; and evidence of rat sarcoma-mitogen-activated protein kinase pathway activation. Results:Of 259 participants (125 female individuals [48.3%]), 102 (39.4%) individuals had NF1 (median [range] age, 34 [18-70] years) and 157 (60.6%) were controls (median [range] age, 40 [15-91] years). CAs were more frequent in individuals with NF1 than controls (48% vs 18%; odds ratio, 4.26; 95% CI, 2.44-7.56) and occurred at a younger age. This association persisted after adjustment for age and sex and in propensity score-matched analyses. Somatic NF1 loss-of-function second hits were identified in 26 of 39 of NF1-associated CAs (67%) and none from controls, indicating biallelic NF1 inactivation. Comprehensive genomic profiling revealed frequent co-occurring activating variants, most commonly in GNAQ. Cell-specific sequencing showed that NF1 second hits arose predominantly in endothelial cells and telocytes, with higher variant allele frequencies in endothelial cells. Immunofluorescence demonstrated increased phosphoextracellular signal-regulated kinase signaling in these vascular cell populations. Conclusions and Relevance:The results of this cross-sectional study suggest that CAs represent a frequent and previously unrecognized vascular manifestation of NF1, which is supported by epidemiological enrichment and mechanistic evidence of biallelic NF1 inactivation in vascular cells. These findings potentially expand the spectrum of NF1-associated neoplasms and establish CAs as a model for NF1-related vasculopathy.

Data on clinical manifestations of neurofibromatosis-Noonan syndrome (NF-NS) remain heterogeneous, with limited validated descriptions. This study aims to better define the clinical and molecular features of NF-NS and compare them with existing literature. Secondary objectives include evaluating inter-rater diagnostic agreement among experienced clinicians and assessing the utility of deep-learning algorithms (Face2Gene® [F2G]). Additionally, we assess the prevalence of congenital heart malformations (CHM) in NF-NS compared to ‘classic’ neurofibromatosis type 1 (NF1). A 9-year, prospective, monocentric study was conducted, involving patients with NF1 pathogenic variants (PVs) and Noonan syndrome-like facial phenotype (NSLFP). Twenty-six patients were enrolled. NSLFP was categorized as ‘suggestive’ in 69

BACKGROUND:Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients. METHODS:We investigated a large, well-phenotyped NF1 cohort. RESULTS:We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants. CONCLUSION:The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.

The access to next-generation sequencing, primarily performed for therapeutic purposes, has considerably increased in the real-time clinical practice in pediatric malignancies. Using germline DNA as a matched reference, this approach is also a unique opportunity to detect alterations in medically actionable genes (named "additional data"). The main objective of this project was to estimate the frequency of such genetic predisposition discoveries among children and adolescents with relapsing or refractory cancer. Among 791 children included in MAPPYACTS “MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification” study, germline DNA exome sequencing was available for 674 patients with many distinct cancer types. Informed consent was obtained to disclose genetic findings if an actionable predisposition was detected. A multidisciplinary germline molecular board established the list of genes to be looked at, including 184 cancer predisposition genes with consensual surveillance guidelines, and 49 non cancer genes belonging to the ACMG Secondary Findings v3.1 list. Bioinformatic analysis included two different indel variant calling (Varscan and Haplotypecaller), quality controls and filters to ensure high-confidence variant calls, ClinVar annotations for pathological classification and in-silico function assessment by computational prediction (with several tools including CADD, SpliceAI and SPiP). Expert biologists have evaluated the pathogenicity of genetic variations with the use of genetic databases, computational predictions and medical literature. Among 184 cancer genes, 16 607 genetic variants have emerged. Twenty-five per cent of them were classified as unknown significance corresponding to a median of 7 (0;47) variants/patient and 8% of variants were retained as likely pathogenic or pathogenic variant (LPV/PV). Thus, 132 patients (19.6%) carried one LPV/PV variant among 53 cancer genes. According to inheritance patterns (we retained heterozygous variant for dominant disease and only biallelic events for recessive disease), genetic counselling was recommended for 58 patients (8.6%). Only two patients had two different cancer predisposition. The most frequently involved genes were TP53 (n=16), DICER1 (n=5), NF1 (n=4) and BRCA1 (n=4). Those identified genetic predispositions to cancer corresponded to the expected tumor spectrum in 50% of cases and were previously known in 38% of families. Furthermore, 10 patients (1.5%) were germline carriers of LPV/PV in genes involved in other genetic conditions (n=6 for cardiopathy; n=2 familial hypercholesterolemia; n=2 transthyretin amyloidosis). A specific evaluation of exome sequenced for therapeutic purposes provides germline information that could be actionable for 10.1% of families to improve cancer prevention or manage some other genetic condition. The psychological impact induced by the return of secondary findings to families will be investigated. Tiphaine Adam de Beaumais, Yahia Adnani, Léa Guerrini-Rousseau, Samuel Abbou, Cécile Acquaviva-Bourdain, Pablo Berlanga, Adeline Bonnard, Gaelle Bougeard, Franck Bourdeaut, Nelly Burnichon, Sandrine Caputo, Alain Carrié, Olivier Caron, Hélène Cavé, Albain Chansavang, Nadège Corradini, Sophie Cotteret, Philippe Denizeau, Alice Fievet, Mathilde Filser, Marion Gauthier-Villars, Birgit Geoerger, Nadim Hamzaoui, Edwige Kasper, Florence Kyndt, Ludovic Lacroix, Jessica Le Gall, Julien Masliah-Planchon, Laurence Pacot, Cécile Pagan, Mélanie Pagès, Béatrice Parfait, Eric Pasmant, Gaelle Pierron, Pascale Richard, Nathalie Roux-Buisson, Cécile Saint-Martin, Hela Sassi, Gudrun Schleiermacher, Renaud Touraine, Nancy Uhrhammer, Dominique Vidaud, Laurence Brugières, Gilles Vassal, Etienne Rouleau, Yoann Vial, Lisa Golmard, Odile Cabaret. Genetic predisposition discoveries of clinical utility by exome sequencing performed for therapeutic purposes in children with relapsing or refractory cancer in the MAPPYACTS study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A006.

Neurofibromatosis type -1 is a genetic disorder caused by loss -of -function variants in the tumorsuppressor NF1. Approximately 4% to 11% of neurofibromatosis type -1 patients have a NF1 locus complete deletion resulting from nonallelic homologous recombination between low copy repeats. Codeleted genes probably account for the more severe phenotype observed in NF1-deleted patients. This genotype -phenotype correlation highlights the need for a detailed molecular description. A droplet digital PCR (ddPCR) set along the NF1 locus was designed to delimitate the three recurrent NF1 deletion breakpoints. The ddPCR was tested in 121 samples from nonrelated NF1-deleted patients. Classification based on ddPCR versus multiplex ligation -dependent probe amplification (MLPA) was compared. In addition, microsatellites were analyzed to identify parental origin of deletions. ddPCR identified 77 type -1 (64%), 20 type -2 (16%), 7 type -3 (6%), and 17 atypical deletions (14%). The results were comparable with MLPA, except for three atypical deletions misclassified as type -2 using MLPA, for which the SUZ12 gene was not deleted. A significant maternal bias (25 of 30) in the origin of deletions was identified. This study proposes a fast and efficient ddPCR quantification to allow fine NF1 deletion classification. It indicates that ddPCR can be implemented easily into routine diagnosis to complement the techniques dedicated to NF1 point variant identification. This new tool may help unravel the genetic basis conditioning phenotypic variability in NF1-deleted patients and offer tailored genetic counseling. (J Mol Diagn 2024, 26: 150-157; https://doi.org/10.1016/j.jmoldx.2023.11.005)

We report our 5-year experience in neurofibromatosis type 1 prenatal diagnosis (PND): 205 PNDs in 146 women (chorionic villus biopsies, 88% or amniocentesis, 12%). The NF1 variant was present in 85 (41%) and absent in 122 (59%) fetuses. Among 205 pregnancies (207 fetuses), 135 were carried to term (119 unaffected and 16 NF1 affected children), 69 pregnancy terminations (affected fetuses), 2 miscarriages, and 1 in utero death. The majority of PND requests came from parents with sporadic NF1. We describe two PNDs in women with mosaic NF1. In both families, direct PND showed the absence of the maternal NF1 variant in the fetus. However, microsatellite markers analysis showed that the risk haplotype had been transmitted. These rare cases of germline mosaicism illustrate the pitfall of indirect PND. Our study illustrates the crucial consequences of PND for medical and genetic counseling decisions. We also point to the challenges of germline mosaics.

Background: Neurofibromatosis type 1 (NF1) is characterized by the highly variable and unpredictable development of benign peripheral nerve sheath tumors named cutaneous (cNFs), subcutaneous (scNFs), and plexiform (pNFs) neurofibromas.Objectives: A significant genetic component in the variability of neurofibroma incidence was evidenced, but without the influence of the causative NF1 gene pathogenic variant. To identify neurofibroma modifier genes, a NF1 patient database was developed.Methods: All patients were phenotypically evaluated by a medical practitioner using a standardized questionnaire and the causal NF1 variant identified. We enrolled 1,333 NF1 patients who were genotyped for more than 7 million common variants.Results: Genome-wide association case-only study identified a significant association in 9q21.33 for the pNFs phenotype in the discovery cohort. Twelve, three, and four regions suggestive of association at the 10-6 threshold were identified for pNFs, cNFs, and scNFs, respectively. Evidence of replication was observed for four, two, and six loci, including 168 candidate modifier protein-coding genes. Among the candidate modifier genes, some were implicated in the RAS-MAPK pathway, cell cycle control, and myelination. Using an original CRISPR/Cas9-based functional assay, we confirmed GAS1 and SPRED2 as pNFs and scNFs candidate modifiers, as their inactivation specifically affected NF1-mutant Schwann cells growth.Conclusion: Our study may shed new light on the pathogenesis of NF1-associated neurofibromas and will hopefully contribute to the development of personalized care for this deleterious and life-threatening condition.

Introduction Le syndrome neurofibromatose de type 1 (NF1)-Noonan constitue une variante phénotypique rare de NF1 caractérisée par l’association de particularités morphologiques faciales de type Noonan à une NF1. Sa prévalence et ses manifestations cliniques restent peu évaluées. Aucune recommandation en termes de prise en charge médicale spécifique n’est établie, à l’inverse des autres RASopathies. Matériel et méthodes Il s’agit d’une étude de cohorte observationnelle rétrospective monocentrique de patients atteints de syndrome NF1-Noonan, vus entre 2012 et 2023. Le diagnostic était validé consensuellement par un comité de 6 généticiens référents des RASopathies. Les objectifs principaux étaient : (i) décrire les manifestations dermatologiques, neurologiques, oculaires, orthopédiques, cardiaques et vasculaires périphériques et les comparer aux données exhaustives de la littérature internationale, (ii) rechercher un éventuel surrisque de cardiopathie congénitale par rapport à la NF1 « classique », sans phénotype Noonan, et (iii) rechercher une éventuelle corrélation génotype (NF1)/phénotype et un éventuel VP portant sur 24 autres gènes des RASopathies. Résultats Vingt-six patients étaient inclus, de sexe-ratio H/F équilibré et d’âge médian 10 ans (6–48). La revue de la littérature identifiait 321 cas de syndrome NF1-Noonan. Les principales anomalies morphologiques faciales de type Noonan, une macrocéphalie et une petite taille étaient respectivement présentes dans 54 %, 42 % et 23 % des cas. Il existait un risque statistiquement augmenté de pectus excavatum, de malformation cardiovasculaire et d’anomalies électrocardiographiques par rapport à la NF1 « classique » avec des prévalences respectives de 61,5 % vs 1 % (p<0,001), 19,2 % vs 4 % (p=0,019) et 8,7 % vs 0,2 % (p=0,012). Les données compilées de la littérature attestaient également d’un risque augmenté de malformations cardiovasculaires dans 36,8 % des cas et plus particulièrement de sténose valvulaire pulmonaire dans près d’un quart des cas. La prévalence de VPs faux-sens NF1 était significativement augmentée dans la cohorte et les données de la littérature par rapport à la NF1 « classique », respectivement 38,5 % et 61,4 % vs 9,2 % (p<0,001). Aucun autre VP des autres gènes des RASopathies ni corrélation génotype/phénotype n’étaient mis en évidence au sein de la cohorte. Discussion Notre étude confirme que le syndrome NF1-Noonan constitue une variante phénotypique rare de NF1, principalement marqué par des variantes morphologiques faciales de type Noonan et un pectus excavatum. Il est significativement associé à un surrisque de malformations cardiovasculaires congénitales par rapport à la NF1 « classique » et pourrait faire recommander un avis systématique cardiologique précoce, une échographie cardiaque et un électrocardiogramme, à la différence de la NF1 « classique ». Conclusion Notre étude confirme que le syndrome NF1-Noonan est associé à un risque augmenté de malformations cardiovasculaires congénitales.

Neurofibromatosis type-1 is a genetic disorder caused by loss-of-function variants in the tumor-suppressor NF1. Approximately 4% to 11% of neurofibromatosis type-1 patients have a NF1 locus complete deletion resulting from nonallelic homologous recombination between low copy repeats. Codeleted genes probably account for the more severe phenotype observed in NF1-deleted patients. This genotype-phenotype correlation highlights the need for a detailed molecular description. A droplet digital PCR (ddPCR) set along the NF1 locus was designed to delimitate the three recurrent NF1 deletion breakpoints. The ddPCR was tested in 121 samples from nonrelated NF1-deleted patients. Classification based on ddPCR versus multiplex ligation-dependent probe amplification (MLPA) was compared. In addition, microsatellites were analyzed to identify parental origin of deletions. ddPCR identified 77 type-1 (64%), 20 type-2 (16%), 7 type-3 (6%), and 17 atypical deletions (14%). The results were comparable with MLPA, except for three atypical deletions misclassified as type-2 using MLPA, for which the SUZ12 gene was not deleted. A significant maternal bias (25 of 30) in the origin of deletions was identified. This study proposes a fast and efficient ddPCR quantification to allow fine NF1 deletion classification. It indicates that ddPCR can be implemented easily into routine diagnosis to complement the techniques dedicated to NF1 point variant identification. This new tool may help unravel the genetic basis conditioning phenotypic variability in NF1-deleted patients and offer tailored genetic counseling.

Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS–mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1 -deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1 -deficient SSPCs adopted a fibrotic fate, NF1 -deficient Schwann cells produced critical paracrine factors including transforming growth factor–β and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1 -deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.

Introduction Depuis 2020, les plateformes, AURAGEN (Sud) et SeqOIA (Nord), permettent le séquençage du génome entier dans le cadre du diagnostic. En dermatologie, trois pré-indications ont été retenues : neurofibromatoses, génodermatose cliniquement identifiée et dont le diagnostic moléculaire reste incomplet (ex : ichtyose), ou dont le gène n’est pas analysé sur un panel en France (ex : cutis laxa) et génodermatose dont le phénotype ne permet pas d’orienter l’analyse moléculaire. Rappelons que les panels utilisés en dermatologie permettent de résoudre 80 % des dossiers soumis. Nous analysons, ici, les indications et les résultats et identifions certains des écueils rencontrés après 4 ans de pratique. Matériel et méthodes Analyse rétrospective des données clinicobiologiques des dossiers acceptés pour séquençage du génome entier sur les deux plateformes. Ont été analysés les indications, les résultats moléculaires, les dossiers conclusifs et les dossiers non conclusifs. Résultats Depuis 2020, les analyses de 163 dossiers ont été rendues (Auragen=58 ; SeqOIA=105). Les motifs d’analyse étaient : panel ciblé non conclusif (n=104), second variant non identifié (n=20), génome entier de première intention (n=36). Les principaux diagnostics étaient : dysplasie ectodermique et incontinentia pigmenti (n=26), neurofibromatose (n=19), anomalie du tissu conjonctif et cutis laxa, (n=14), albinisme (n=12), anomalie des phanères (ongles ou cheveux, n=12), taches café au lait isolées (n=11). L’analyse moléculaire a été conclusive dans 59 dossiers dont: dysplasie ectodermique (n=16/20), neurofibromatose (n=8/19), anomalie du tissu conjonctif et cutis laxa, (n=4/14), albinisme (n=6/12), anomalie des phanères (ongles ou cheveux, n=8/12). Elle n’a jamais été conclusive pour les taches café au lait isolées ou l’incontinentia pigmenti.L’analyse moléculaire par génome entier a redressé ou permis le diagnostic clinique (n=3 ; cutis laxa et dyschromatose au lieu d’ichtyose et poïkilodermie et association trichothiodystrophie-xeroderma pigmentosum), l’identification de mécanismes moléculaires complexes (n=3) ou des gènes jamais associés à une pathologie humaine (n=2). Discussion Au terme de cette première étape, nous pouvons souligner l’importance centrale d’une description phénotypique précise, du partenariat clinicien–biologiste et les difficultés inhérentes aux diagnostics prédéfinis (codes HPO par exemple). L’absence d’identification de variant délétère (2/3 des patients) illustre la complexité des mécanismes moléculaires en cause, la possibilité de formes mosaïques et l’importance de la discussion des dossiers. Conclusion Si l’analyse du génome entier a enregistré de nombreux résultats positifs, la concertation, la caractérisation phénotypique et les mécanismes moléculaires complexes sont au cœur des futurs succès.

La neurofibromatose de type 1 (NF1) est causée par une mutation du gène NF1, suppresseur de tumeur. Certaines caractéristiques anthropométriques associées à la NF1 ont été rapportées (c.-à-d., une macrocéphalie, petite taille), sans étude démonstrative robuste. L’objectif était d’étudier la prévalence de l’obésité et du surpoids chez les adultes atteints de NF1, en comparaison à la population générale. Cette étude rétrospective a inclus tous les adultes atteints de NF1 suivis dans le centre de référence (CERENEF), à partir de la base de données du réseau français des maladies rares de la peau (BAMARA) depuis sa création jusqu’en septembre 2022. Les données démographiques et cliniques étaient recueillies, et l’indice de masse corporelle (IMC) calculé. Les résultats ont été comparés à ceux de la population générale (étude française Obépi-Roche 2020 de la Ligue Contre l’Obésité). Au total, 1254 patients dont 713 femmes (57 %) ont été inclus. L’âge moyen était de 39 ans (déviation standard [DS] 14,5). La population NF1 était significativement plus jeune (p < 0,001) et féminine (p = 0,031). L’IMC moyen était significativement plus faible dans la population NF1 (24,1 vs 25,5 kg/m2, IC95 [23,9–24,4]). Les prévalences du surpoids (IMC entre 25 et 30 kg/m2) et de l’obésité (IMC ≥ 30 kg/m2) étaient significativement plus faibles dans l’ensemble de la population NF1 : 24,4 % vs 30,3 %, IC95 % [22,1–26,9,0], p < 0,001, et 10,4 % vs 17,0 %, IC95 % [8,8–12,2], p < 0,001, respectivement. Ces différences étaient significatives indépendamment du sexe (p < 0,001). Chez les individus en surpoids ou obèses, les répartitions des différentes catégories socioprofessionnelles étaient similaires à celle des témoins, à l’exception de la catégorie « employés » (secteurs public et privé) dont la proportion était supérieure en population générale (p = 0,008). La taille moyenne était significativement plus basse dans la population NF1 (p < 0,001). Les analyses uni- et multivariées ont montré une association entre l’obésité et un nombre important de neurofibromes cutanés (NFc, > 100) (OR : 1,99, IC95 % [1,03–3,84], p = 0,04). Cette étude confirme le profil anthropométrique des adultes vivant avec une NF1, caractérisé par une plus petite taille et un plus faible IMC. Par ailleurs, la présence d’un nombre important de NFc semble associée à un IMC plus élevé. Alors qu’un hypermétabolisme a été décrit dans la NF1 (via l’augmentation de RAS-GTP puis celle de d’ATP), celui-ci est connu pour favoriser le développement de cancers. Concernant les NFc, une proportion significative de ces tumeurs bénignes sont lipomateuses et toutes sécrètent de la leptine (sécrétée par les adipocytes). Ces éléments confirment le probable lien entre NFc et adipocytes. Le profil anthropométrique retrouvé dans la NF1 pourrait être lié à un hypermétabolisme. La recherche d’une éventuelle corrélation génotype/phénotype pourrait apporter un nouvel éclairage.

Supplementary Figure 1 Legend from Characterization of a Germ-Line Deletion, Including the Entire <i>INK4/ARF</i> Locus, in a Melanoma-Neural System Tumor Family: Identification of <i>ANRIL</i>, an Antisense Noncoding RNA Whose Expression Coclusters with <i>ARF</i>

PDF file 161K, A simplified representation of the three different Wnt signalling pathways: the canonical pathway, the planar cell polarity pathway, and the Wnt/calcium pathway. In the absence of Wnt ligand, the 'destruction complex' composed of the core proteins Axin, adenomatous polyposis coli (APC), and glycogen synthase kinase-3 (GSK3) rapidly phosphorylates cytosolic beta-catenin, targeting it for subsequent proteasome-mediated destruction. Binding of Wnt to Frizzled (FZD) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates the cytosolic protein Dishevelled (DVL), leading to inhibition of the destruction complex. The resulting accumulated beta-catenin can then translocate to the nucleus to activate Wnt-responsive target genes regulated by lymphoid enhancer factor (LEF) and T cell factor (TCF) family transcription factors, leading to various cellular effects. The secreted inhibitor Dickkopf (DKK) can antagonize Wnt signalling by competitively binding to LRP5/6. Secreted FZD-related proteins (SFRPs) and Wnt inhibitory factor (WIF) are thought to antagonize Wnt signalling by sequestering Wnt ligand in the extracellular space. Binding of Wnt isoforms to FZD can trigger beta-catenin-independent downstream signalling events, other so-called non-canonical Wnt pathways that do not require the transcriptional activity of beta-catenin. One branch of non-canonical pathways involves the activation of RHO and RAC small G proteins to regulate the actin cytoskeleton. DVL-associated activator of morphogenesis 1 (DAAM1), when complexed with DVL and RHO, acts through the regulation of RHO-associated protein kinases (ROCK) and the DVL-RAC GTPase complex to affect actin remodelling. Another branch, when activated, is defined by a phospholipase C (PLC)-mediated increase in intracellular Ca2+ levels and Ca2+ fluxes that lead to the activation of Ca2+/calmodulin-dependent protein kinase (CaMK), protein kinase C (PKC), and nuclear factor of activated T cells (NFAT)

PDF file 71K, mRNA expression of 24 identified genes in four sporadic MPNSTs

PDF file 55K, Clinical and histological characteristics of the 16 patients with MPNSTs