Gene Summary

Gene:NF1; neurofibromin 1
Aliases: WSS, NFNS, VRNF
Summary:This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NF1 (cancer-related)

Antonopoulos D, Tsilioni I, Balatsos NAA, et al.
The mast cell - neurofibromatosis connection.
J Biol Regul Homeost Agents. 2019 May-Jun,; 33(3):657-659 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1/3000 individuals worldwide. It results from germline mutations of the neurofibromin gene and it is fully penetrant by the age of 5. Neurofibromin is a 2818 amino acid protein that is produced in many cell types, but its levels are especially high in the nervous system.

Oppel F, Tao T, Shi H, et al.
Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies.
PLoS Genet. 2019; 15(4):e1008039 [PubMed] Free Access to Full Article Related Publications
The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.

Lombard DB, Cierpicki T, Grembecka J
Combined MAPK Pathway and HDAC Inhibition Breaks Melanoma.
Cancer Discov. 2019; 9(4):469-471 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
In this issue, Maertens and colleagues demonstrate that HDAC3 inhibition potentiates the effects of MAPK pathway inhibitors in melanoma, including difficult-to-treat

Trevisson E, Morbidoni V, Forzan M, et al.
The Arg1038Gly missense variant in the NF1 gene causes a mild phenotype without neurofibromas.
Mol Genet Genomic Med. 2019; 7(5):e616 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by inactivating mutations of the NF1 gene. The wide allelic heterogeneity of this condition, with more than 3,000 pathogenic variants reported so far, is paralleled by its high clinical variability, which is observed even within the same family. The definition of genotype-phenotype correlations has been hampered by the complexity of the NF1 gene and, although a few exceptions have been recognized, the clinical course remains unpredictable in most patients.
METHODS: Sequencing of NF1 in patients with cafè-au-lait spots identified the c.3112A>G variant. RNA analysis and a minigene assay were employed to investigate splicing.
RESULTS: Here we report a novel genotype-phenotype correlation in NF1: the identification of the missense variant NM_000267.3:c.3112A>G p.(Arg1038Gly) in seven individuals from two unrelated families with a mild phenotype. All the patients manifest cafè-au-lait spots without neurofibromas or other NF1-associated complications, and Noonan syndrome features in most cases. The missense variant was not previously reported in available databases, segregates with the phenotype and involves a highly conserved residue. Both a minigene assay and patient's RNA analysis excluded an effect on splicing.
CONCLUSION: Our data support the correlation of the p.Arg1038Gly missense substitution with the cutaneous phenotype without neurofibromas or other complications. This finding may have relevant implications for patients and genetic counseling, but also to get insights into the function of neurofibromin.

Lee MJ, Tsai YJ, Lin MY, et al.
Calebin-A induced death of malignant peripheral nerve sheath tumor cells by activation of histone acetyltransferase.
Phytomedicine. 2019; 57:377-384 [PubMed] Related Publications
BACKGROUND: Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. The malignant peripheral nerve sheath tumor (MPNST), transformed from NF1 related plexiform neurofibroma, is a rapidly growing and highly invasive tumor. No effective chemotherapeutic agent is currently available. Calebin-A is a derivative from turmeric Curcuma longa. Given the anti-inflammatory and anticancer potentials of curcumin, whether Calebin-A also had the tumoricidal effect upon MPNST cells is still elusive.
PURPOSE: To determine whether Calebin-A has the potential for anti-MPNST effect.
METHODS: The MTT and FACS analysis of normal Schwann (HSC) and MPNST cells have been employed to determine the tumoricidal effect of Calebin-A. The expression of the signal pathway molecules was assessed by Western blotting. The CHIP with quantitative PCR assay was performed to quantify the promoter DNA binding to acetylated histone 3 (acetyl H3). The enzyme activities of histone acetyltransferase (HAT) and deacetylase (HDAC) have been evaluated by commercial kits. The measurements of tumor size of the xenograft mouse model were also performed.
RESULTS: Calebin-A inhibited the proliferation of MPNST and primary neurofibroma cells in a dose-dependent manner. The flow cytometry analysis of the MPNST cells after treatment of 25 μm of Calebin-A demonstrated an increase of population in the G0/G1 phase but decrease in G2/M phase. Before treatment, the expression of Axl, Tyro3, and acetyl H3 was significantly higher in MPNST cells when compared to HSC. The expression of phosphorylated-AKT, -ERK1/2, survivin, hTERT, and acetyl H3 proteins were reduced after treatment. The CHIP assay shows the promoter DNA copies of survivin (BRIC5) and hTERT genes are significantly reduced post-treatment. The enzyme activity of HAT was significantly reduced, but not that of HDAC. Two HAT inhibitors, epigallocatechin-3-gallate (EGCG) and anacardic acid (AA) have also demonstrated a significant inhibitory effect on MPNST cells. Finally, the measurements of tumor size showed a significant reduction of the xenograft tumors after treatment of Calebin-A.
CONCLUSION: Both in vitro and in vivo studies showed Calebin-A could inhibit the proliferation of MPNST with suppression of survivin and hTERT. The reduced expression of these two factors might be through the epigenetic histone modification resulting from the decreased activity of HAT.

Zhou R, Shi C, Tao W, et al.
Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations.
Clin Cancer Res. 2019; 25(12):3548-3560 [PubMed] Related Publications
PURPOSE: Unlike advances in the genomics-driven precision treatment of cutaneous melanomas, the current poor understanding of the molecular basis of mucosal melanomas (MM) has hindered such progress for MM patients. Thus, we sought to characterize the genomic landscape of MM to identify genomic alterations with prognostic and/or therapeutic implications.
EXPERIMENTAL DESIGN: Whole-genome sequencing (WGS) was performed on 65 MM samples, including 63 paired tumor blood samples and 2 matched lymph node metastases, with a further droplet digital PCR-based validation study of an independent MM cohort (
RESULTS: Besides the identification of well-recognized driver mutations of
CONCLUSIONS: Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution and identifies genomic aberrations that could facilitate the delivery of precision cancer treatments.

Margraf RL, VanSant-Webb C, Mao R, et al.
NF1 Somatic Mutation in Dystrophic Scoliosis.
J Mol Neurosci. 2019; 68(1):11-18 [PubMed] Related Publications
Scoliosis is a common manifestation of neurofibromatosis type 1, causing significant morbidity. The etiology of dystrophic scoliosis in neurofibromatosis type 1 is not fully understood and therapies are lacking. Somatic mutations in NF1 have been shown in tibial pseudarthrosis providing rationale for similar processes in neurofibromatosis type 1-associated dystrophic scoliosis. Spinal samples from surgical procedures with matched peripheral blood of two individuals with neurofibromatosis type 1 and dystrophic scoliosis were obtained and DNA extracted. Next generation sequencing of various spinal sections as well as the germline/blood sample were performed using a RASopathy gene panel (includes the NF1 gene). Variants were compared between the spinal tissue samples and the germline data. In addition, the next generation sequencing allele frequency data were used to detect somatic loss of heterozygosity. All samples had a detected potentially inactivating NF1 germline mutation. Both individuals demonstrated an allelic imbalance inclusive of NF1 in the next generation sequencing data. In addition, for the same two individuals, there was an increase in the % variant reads for the germline mutation in some of the surgical spinal samples corresponding to the allelic imbalance. Contra analysis did not show any deletion in Chromosome 17 next generation sequencing data. Microarray analysis verified somatic copy neutral loss of heterozygosity for these two individuals for the majority of the chromosome 17 q-arm, inclusive of the NF1 gene. These results suggest that the cause of dystrophic scoliosis is multifactorial and that a somatic NF1 mutation contributes to the etiology.

Weindorf SC, Taylor AS, Kumar-Sinha C, et al.
Metastatic castration resistant prostate cancer with squamous cell, small cell, and sarcomatoid elements-a clinicopathologic and genomic sequencing-based discussion.
Med Oncol. 2019; 36(3):27 [PubMed] Related Publications
Histologic variants are uncommon but well reported amongst cases of prostatic adenocarcinoma, including those in the setting of hormonal and/or chemoradiation therapy and castration resistance. However, the spectrum of morphologic phenotypes and molecular alterations present in such histologic variants are still incompletely understood. Herein, we describe a case of metastatic prostatic adenocarcinoma with hormonal and chemoradiation therapy-associated differentiation, displaying a combination of squamous cell, small cell, and sarcomatoid elements. The morphologic, immunohistochemical, and molecular observations are discussed with attention given to the gene alterations present, including in TP53, NF1, AR, PTEN, and RB1. Finally, we will compare our findings with those observed in uncommonly reported similar cases so as to detail the molecular underpinnings of such processes which may carry therapeutic implications.

Yi D, Xu L, Luo J, et al.
Germline TP53 and MSH6 mutations implicated in sporadic triple-negative breast cancer (TNBC): a preliminary study.
Hum Genomics. 2019; 13(1):4 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Germline BRCA1/2 prevalence is relatively low in sporadic triple-negative breast cancer (TNBC). We hypothesized that non-BRCA genes may also have significant germline contribution to Chinese sporadic TNBC, and the somatic mutational landscape of TNBC may vary between ethnic groups. We therefore conducted this study to investigate germline and somatic mutations in 43 cancer susceptibility genes in Chinese sporadic TNBC.
PATIENTS AND METHODS: Sixty-six Chinese sporadic TNBC patients were enrolled in this study. Germline and tumor DNA of each patient were subjected to capture-based next-generation sequencing using a 43-gene panel. Standard bioinformatic analysis and variant classification were performed to identify deleterious/likely deleterious germline mutations and somatic mutations. Mutational analysis was conducted to identify significantly mutated genes.
RESULTS: Deleterious/likely deleterious germline mutations were identified in 27 (27/66, 40.9%) patients. Among the 27 patients, 9 (9/66, 13.6%) were TP53 carriers, 5 (5/66, 7.6%) were MSH6 carriers, and 5 (5/66, 7.6%) were BRCA1 carriers. Somatic mutations were identified in 64 (64/66, 97.0%) patients. TP53 somatic mutations occurred in most of the patients (45/66, 68.2%) and with highest mean allele frequency (28.1%), while NF1 and POLE were detected to have the highest mutation counts.
CONCLUSIONS: Our results supported our hypotheses and suggested great potentials of TP53 and MSH6 as novel candidates for TNBC predisposition genes. The high frequency of somatic NF1 and POLE mutations in this study showed possibilities for clinical benefits from androgen-blockade therapies and immunotherapies in Chinese TNBC patients. Our study indicated necessity of multi-gene testing for TNBC prevention and treatment.

Zhang X, Bai Q, Xu Y, et al.
Molecular profiling of the biphasic components of hepatic carcinosarcoma by the use of targeted next-generation sequencing.
Histopathology. 2019; 74(6):944-958 [PubMed] Related Publications
AIMS: To better understand the tumourogenesis and molecular features of hepatic carcinosarcoma (HCS).
METHODS AND RESULTS: We selected 13 cases of HCS, including the clinicopathological and immunohistochemical features, and analysed the molecular alterations in separately microdissected carcinomatous and sarcomatous components in eight cases by using targeted next-generation sequencing with a panel of 329 cancer-related genes. As a result, transitional areas were observed between the two components of HCS in all cases. Concordance and overlap in genetic alterations were identified in the two histological components of the eight HCS patients, indicating the clonal relatedness of the two tumour components. The most common gene alterations found in both components were TP53 (75%, 6/8) and NF1/2 (38%, 3/8) mutations and VEGFA amplification (25%, 2/8), which may be strongly associated with HCS tumorigenesis. Unique mutations and amplifications found only in one component were also identified. Amplifications involving MET (38%, n = 3/8) and PDGFRA (25%, n = 2/8) were present only in the sarcomatous components, whereas mutation affecting ERBB4 (25%, n = 2/8) and amplifications of CCND1 and FGF3/4/19 (38%, n = 3/8) were present only in the carcinomatous components, indicating their involvement in the clonal evolution of HCS. Furthermore, multiple potential therapeutic targets were identified for HCS.
CONCLUSIONS: Our findings indicate that HCS could have been of monoclonal origin, and that the diverse clonal evolution might be driven by special molecular alterations in each tumour component. Our results also identify multiple therapeutic targets of HCS, which are valuable for the personalised treatment of HCS.

Darrigo Júnior LG, Lira RCP, Fedatto PF, et al.
MicroRNA profile of pediatric pilocytic astrocytomas identifies two tumor-specific signatures when compared to non-neoplastic white matter.
J Neurooncol. 2019; 141(2):373-382 [PubMed] Related Publications
PURPOSES: Pilocytic astrocytoma (PA) is a low-grade neoplasm frequently found in childhood. PA is characterized by slow growth and a relatively good prognosis. Genetic mechanisms such as activation of MAPK, BRAF gene deregulation and neurofibromatosis type 1 (NF1) syndrome have been associated with PA development. Epigenetic signature and miRNA expression profile are providing new insights about different types of tumor, including PAs.
METHODS: In the present study we evaluated global miRNA expression in 16 microdissected pediatric PA specimens, three NF1-associated PAs and 11 cerebral white matter (WM) samples by the microarray method. An additional cohort of 20 PAs was used to validate by qRT-PCR the expression of six miRNAs differentially expressed in the microarray data.
RESULTS: Unsupervised hierarchical clustering analysis distinguished one cluster with nine PAs, including all NF1 cases and a second group consisting of the WM samples and seven PAs. Among 88 differentially expressed miRNAs between PAs and WM samples, the most underexpressed ones regulate classical pathways of tumorigenesis, while the most overexpressed miRNAs are related to pathways such as focal adhesion, P53 signaling pathway and gliomagenesis. The PAs/NF1 presented a subset of underexpressed miRNAs, which was also associated with known deregulated pathways in cancer such as cell cycle and hippo pathway.
CONCLUSIONS: In summary, our data demonstrate that PA harbors at least two distinct miRNA signatures, including a subgroup of patients with NF1/PA lesions.

D'Angelo F, Ceccarelli M, Tala, et al.
The molecular landscape of glioma in patients with Neurofibromatosis 1.
Nat Med. 2019; 25(1):176-187 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Niemeyer CM
JMML genomics and decisions.
Hematology Am Soc Hematol Educ Program. 2018; 2018(1):307-312 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (

Vo TM, Burchett R, Brun M, et al.
Effects of nuclear factor I phosphorylation on calpastatin (
J Biol Chem. 2019; 294(4):1173-1188 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Malignant glioma (MG) is the most lethal primary brain tumor. In addition to having inherent resistance to radiation treatment and chemotherapy, MG cells are highly infiltrative, rendering focal therapies ineffective. Genes involved in MG cell migration and glial cell differentiation are up-regulated by hypophosphorylated nuclear factor I (NFI), which is dephosphorylated by the phosphatase calcineurin in MG cells. Calcineurin is cleaved and thereby activated by calpain proteases, which are, in turn, inhibited by calpastatin (CAST). Here, we show that the

Lim SZ, Ng CCY, Rajasegaran V, et al.
Genomic profile of breast sarcomas: a comparison with malignant phyllodes tumours.
Breast Cancer Res Treat. 2019; 174(2):365-373 [PubMed] Related Publications
PURPOSE: We aimed to investigate the genomic profile of breast sarcomas (BS) and compare with that of malignant phyllodes tumours (MPT).
METHODS: DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) specimens from 17 cases of BS diagnosed at Singapore General Hospital from January 1991 to December 2014. Targeted deep sequencing and copy number variation (CNV) analysis on 16 genes, which included recurrently mutated genes in phyllodes tumours and genes associated with breast cancer, were performed on these samples. Genetic alterations (GA) observed were summarised and analysed.
RESULTS: Nine cases met the quality control requirements for both targeted deep sequencing and CNV analysis. Three (33.33%) were angiosarcomas and 6 (66.67%) were non-angiosarcomas. In the non-angiosarcoma group, 83.33% (n = 5) of the patients had GA in the TERT gene. The other commonly mutated genes in this group of tumours were MED12 (n = 4, 66.67%), BCOR (n = 4, 66.67%), KMT2D (n = 3, 50%), FLNA (n = 3, 50%) and NF1 (n = 3, 50%). In contrast, none of the angiosarcomas had mutations or copy number alterations in TERT, MED12, BCOR, FLNA or NF1. Eighty percent of patients with GA in TERT (n = 5) had concurrent mutations in MED12. Sixty percent (n = 3) of these cases also demonstrated GA in NF1, PIK3CA or EGFR which are known cancer driver genes.
CONCLUSIONS: The non-angiosarcoma group of BS was found to share similar GA as those described for MPT, which may suggest a common origin and support their consideration as a similar group of tumours with regard to management and prognostication.

Brosseau JP, Liao CP, Wang Y, et al.
NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation.
Nat Commun. 2018; 9(1):5014 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Neurofibromatosis type 1 (NF1) is an autosomal genetic disorder. Patients with NF1 are associated with mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposes them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients, suggesting that NF1 heterozygosity is refractory to at least some cancer types. In two orthogonal mouse models representing NF1- and non-NF1-related tumors, we discover that an Nf1

Summerer A, Schäfer E, Mautner VF, et al.
Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions.
Hum Genet. 2019; 138(1):73-81 [PubMed] Related Publications
Different types of large NF1 deletion are distinguishable by breakpoint location and potentially also by the frequency of mosaicism with normal cells lacking the deletion. However, low-grade mosaicism with fewer than 10% normal cells has not yet been excluded for all NF1 deletion types since it is impossible to assess by the standard techniques used to identify such deletions, including MLPA and array analysis. Here, we used ultra-deep amplicon sequencing to investigate the presence of normal cells in the blood of 20 patients with type-1 NF1 deletions lacking mosaicism according to MLPA. The ultra-deep sequencing entailed the screening of 96 amplicons for heterozygous SNVs located within the NF1 deletion region. DNA samples from three previously identified patients with type-2 NF1 deletions and low-grade mosaicism with normal cells as determined by FISH or microsatellite marker analysis were used to validate our methodology. In these type-2 NF1 deletion samples, proportions of 5.3%, 6.6% and 15.0% normal cells, respectively, were detected by ultra-deep amplicon sequencing. However, using this highly sensitive method, none of the 20 patients with type-1 NF1 deletions included in our analysis exhibited low-grade mosaicism with normal cells in blood, thereby supporting the view that the vast majority of type-1 deletions are germline deletions.

Molosh AI, Shekhar A
Neurofibromatosis type 1 as a model system to study molecular mechanisms of autism spectrum disorder symptoms.
Prog Brain Res. 2018; 241:37-62 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1) is monogenic neurodevelopmental disorder caused by mutation of NF1 gene, which leads to increased susceptibility to various tumors formations. Additionally, majority of patients with NF1 are experience high incidence of cognitive deficits. Particularly, we review the growing number of reports demonstrated a higher incidence of autism spectrum disorder (ASD) in individuals with NF1. In this review we also discuss face validity of preclinical Nf1 mouse models. Then we describe discoveries from these animal models that have uncovered the deficiencies in the regulation of Ras and other intracellular pathways as critical mechanisms underlying the Nf1 cognitive problems. We also summarize and interpret recent preclinical and clinical studies that point toward potential pharmacological therapies for NF1 patients.

Przybylik-Mazurek E, Palen J, Pasternak-Pietrzak K, et al.
Coexistence of neurofibromatosis type 1 with multiple malignant neoplasia.
Neuro Endocrinol Lett. 2018; 39(3):149-155 [PubMed] Related Publications
Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is inherited in autosomal dominant way genetic disorder, with an incidence at birth 1:3000. It is one of the most common congenital disorders. It is characterized by café-au-lait spots, neurofibromas, and less common MPTST and gliomas of the optic nerve. It is caused by germline mutations of the NF1 gene, which acts as tumor suppressor. Inactivation of the gene leads to increased activation of the kinase pathways, and in consequence, uncontrolled proliferation of cells. The disease predisposes to the development of both benign and malignant tumors. Malignant tumors, but not related to the nervous system occur in neurofibromatosis quite rare. The aim of the study is a literature review of NF1, with presentation of a patient with NF1 and coexisting numerous tumors: synchronous somatostatinoma and gastrointestinal stromal tumor with metachronous prostate adenocarcinoma and non-small cell lung carcinoma. And attempt to answer the question if there is a common pathway for oncogenesis of these four tumors.

Iida Y, Salomon MP, Hata K, et al.
Predominance of triple wild-type and IGF2R mutations in mucosal melanomas.
BMC Cancer. 2018; 18(1):1054 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
BACKGROUND: Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment.
METHODS: Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry.
RESULTS: Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002).
CONCLUSIONS: These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

Tsipi M, Poulou M, Fylaktou I, et al.
Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA.
J Neurol Sci. 2018; 395:95-105 [PubMed] Related Publications
Neurofibromatosis Type 1 (NF1) is caused by mutations of the NF1 gene. The aim of this study was to identify the genetic causes underlying the disease, attempt possible phenotype/genotype correlations and add to the NF1 mutation spectrum. A screening protocol based on genomic DNA was established in 168 patients, encompassing sequencing of all coding exons and adjoining introns using a custom targeted next generation sequencing protocol and subsequent confirmation of findings with Sanger sequencing. MLPA was used to detect deletions/duplications and positive findings were confirmed by RNA analysis. All novel findings were evaluated according to ACMG Standards and guidelines for the interpretation of sequence variants with the aid of in-silico bioinformatic tools and family segregation analysis. A germline variant was identified in 145 patients (86%). In total 49 known and 70 novel variants in coding and non-coding regions were identified. Seven patients carried whole or partial gene deletions. NF1 patients, present with high phenotypic variability even in cases where the same germline disease causing variant has been identified. Our findings will contribute to a better knowledge of the genetic causes and the phenotypic expression related to the disease.

Kluwe L, Hagel C, Friedrich RE, et al.
Vitamin D receptor expression and serum 25(OH)D concentration inversely associates with burden of neurofibromas.
Eur J Cancer Prev. 2019; 28(3):220-224 [PubMed] Related Publications
Vitamin D and its receptor may play a role in preventing tumor development and progression. As such antineoplastic effects are expected to be weak and to act over long periods, conditions with increased tumor incidence, such as the neurofibromatosis type 1 (NF1), provide suitable study models. We previously found an inverse correlation of serum 25(OH)D concentration with number of neurofibromas in NF1. Here we aim to further explore the role of the vitamin D receptor. A total of 141 adult NF1 patients were included in the study. For 101 of them, serum vitamin 25(OH)D data were available. From 87 patients, blood samples were obtained in PaxGene tubes containing a reagent to stabilize RNA immediately. mRNA of the vitamin D receptor (VDR) gene (coding for the vitamin D receptor) was measured by means of RT-PCR. Correlation of laboratory data with NF1-related tumors was statistically evaluated. Vitamin D receptor in NF1-tumors was examined by means of immunohistochemistry using an antibody against the vitamin D1 receptor. The number of dermal neurofibromas was significantly inversely correlated with VDR mRNA level and with serum 25(OH)D concentration in NF1 patients. In contrast, plexiform neurofibroma and malignant peripheral nerve sheath tumor did not correlate with these two parameters. Immunostaining did not detect vitamin D receptor in NF1-tumors. Both vitamin D and its receptor may play a role in suppressing the development of neurofibromas. Sustaining 25(OH)D at an adequate level may contribute to controlling neurofibromas and possibly also other tumors. This is especially important for individuals with lower expression of VDR.

Wu-Chou YH, Hung TC, Lin YT, et al.
Genetic diagnosis of neurofibromatosis type 1: targeted next- generation sequencing with Multiple Ligation-Dependent Probe Amplification analysis.
J Biomed Sci. 2018; 25(1):72 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
BACKGROUND: Neurofibromatosis type 1 (NF1) is a dominantly inherited tumor predisposition syndrome that targets the peripheral nervous system. It is caused by mutations of the NF1 gene which serve as a negative regulator of the cellular Ras/MAPK (mitogen-activated protein kinases) signaling pathway. Owing to the complexity in some parts of clinical diagnoses and the need for better understanding of its molecular relationships, a genetic characterization of this disorder will be helpful in the clinical setting.
METHODS: In this study, we present a customized targeted gene panel of NF1/KRAS/BRAF/p53 and SPRED1 genes combined with Multiple Ligation-Dependent Probe Amplification analysis for the NF1 mutation screening in a cohort of patients clinically suspected as NF1.
RESULTS: In this study, we identified 73 NF1 mutations and two BRAF novel variants from 100 NF1 patients who were suspected as having NF1. These genetic alterations are heterogeneous and distribute in a complicated way without clustering in either cysteine-serine-rich domain or within the GAP-related domain. We also detected fifteen multi-exon deletions within the NF1 gene by MLPA Analysis.
CONCLUSIONS: Our results suggested that a genetic screening using a NGS panel with high coverage of Ras-signaling components combined with Multiple Ligation-Dependent Probe Amplification analysis will enable differential diagnosis of patients with overlapping clinical features.

Wilson KM, Mathews-Griner LA, Williamson T, et al.
Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy.
SLAS Technol. 2019; 24(1):28-40 [PubMed] Related Publications
Glioblastoma (GBM) is a lethal brain cancer with a median survival time of approximately 15 months following treatment. Common in vitro GBM models for drug screening are adherent and do not recapitulate the features of human GBM in vivo. Here we report the genomic characterization of nine patient-derived, spheroid GBM cell lines that recapitulate human GBM characteristics in orthotopic xenograft models. Genomic sequencing revealed that the spheroid lines contain alterations in GBM driver genes such as PTEN, CDKN2A, and NF1. Two spheroid cell lines, JHH-136 and JHH-520, were utilized in a high-throughput drug screen for cell viability using a 1912-member compound library. Drug mechanisms that were cytotoxic in both cell lines were Hsp90 and proteasome inhibitors. JHH-136 was uniquely sensitive to topoisomerase 1 inhibitors, while JHH-520 was uniquely sensitive to Mek inhibitors. Drug combination screening revealed that PI3 kinase inhibitors combined with Mek or proteasome inhibitors were synergistic. However, animal studies to test these drug combinations in vivo revealed that Mek inhibition alone was superior to the combination treatments. These data show that these GBM spheroid lines are amenable to high-throughput drug screening and that this dataset may deliver promising therapeutic leads for future GBM preclinical studies.

Ravegnini G, Quero G, Sammarini G, et al.
Gastrointestinal juvenile-like (inflammatory/hyperplastic) mucosal polyps in neurofibromatosis type 1 with no concurrent genetic or clinical evidence of other syndromes.
Virchows Arch. 2019; 474(2):259-264 [PubMed] Related Publications
Gastrointestinal "juvenile-like (inflammatory/hyperplastic) mucosal polyps" (JLIHMPs) have been proposed as a neurofibromatosis type 1 (NF1)-specific gastrointestinal manifestation. Juvenile polyposis syndrome (JPS) has also been reported in a NF1 patient, harboring concurrent NF1 and SMAD4 germline mutations. Additionally, NF1-like cafe-au-lait spots have been described in biallelic mismatch repair deficiency, another condition featuring gastrointestinal polyps. The SMAD4 and BMPR1A genes that are involved in 50-60% of JPS cases have not been investigated in the ~ 20 published cases of NF1-associated JLIHMPs with the exception of the abovementioned patient with concomitant JPS and NF1. NF1 defects have been found in the only two cases exhaustively tested. Therefore, JLIHMP has been questioned as an independent, NF1-specific entity. Incidental associations between NF1 and gastrointestinal polyposes at risk for gastrointestinal carcinoma should not be overlooked, given their implications in terms of clinical surveillance. We describe two patients featuring JLIHMPs in clinically/genetically proven NF1, in the absence of SMAD4 and BMPR1A mutations. In one case, the intervening mucosa was markedly inflamed, unlike JPS. We suggest that JLIHMP probably represents a gastrointestinal lesion specific to NF1.

Isakov O, Wallis D, Evans DG, Ben-Shachar S
Exhaustive non-synonymous variants functionality prediction enables high resolution characterization of the neurofibromin architecture.
EBioMedicine. 2018; 36:508-516 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
BACKGROUND: Neurofibromatosis type I (NF1) is caused by heterozygous loss-of-function variants in the NF1 gene encoding neurofibromin which serves as a tumor suppressor that inhibits RAS signaling and regulates cell proliferation and differentiation. While, the only well-established functional domain in the NF1 protein is the GAP-related domain (GRD), most of the identified non-truncating disease-causing variants are located outside of this domain, supporting the existence of other important disease-associated domains. Identifying these domains may reveal novel functions of NF1.
METHODS: By implementing inferential statistics combined with machine-learning methods, we developed a novel NF1-specific functional prediction model that focuses on nonsynonymous single nucleotide variants (SNVs). The model enables annotating all possible NF1 nonsynonymous variants, thus mapping the range of pathogenic non-truncating variants at the codon level across the NF1 gene.
FINDINGS: The generated model demonstrates high absolute prediction value for missense and splice-site variations (area under the ROC curve of 0.96) outperforming 14 other established models. By reviewing the entire dataset of nonsynonymous variants, two novel domains (Armadillo type fold 1 and 2) were identified as being associated with pathogenicity (OR 1.86; CI 1.04 to 3.34 and OR 2.08; CI 1.08 to 4.04, respectively; P < .05). Specific exons and codons associated with increased pathogenicity were also detected along the gene inside and outside the GRD domain.
INTERPRETATION: The developed model, enabled better prediction of pathogenicity for variants in NF1 gene, as well as elucidation of novel NF1-associated domains in addition to the GRD. FUND: This work was partially supported by the Kahn foundation. DGE is supported by the all Manchester NIHR Biomedical Research Centre (IS-brC-1215-20007).

Wang DS, Liu ZX, Lu YX, et al.
Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer.
Gut. 2019; 68(7):1152-1161 [PubMed] Related Publications
OBJECTIVE: To monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC).
DESIGN: Targeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+  to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes.
RESULTS: The results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of
CONCLUSION: Longitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.

Pan Y, Yuan C, Cheng C, et al.
Frequency and clinical significance of NF1 mutation in lung adenocarcinomas from East Asian patients.
Int J Cancer. 2019; 144(2):290-296 [PubMed] Related Publications
NF1 is a tumor suppressor gene that negatively regulates Ras signaling. NF1 deficiency plays an important role in carcinogenesis. To investigate the frequency and clinical significance of NF1 mutation, we examined mutation status of NF1, TP53, LKB1 and RB1 in 704 surgically resected lung adenocarcinomas from East Asian patients using semiconductor-based Ion Torrent sequencing platform. Common driver events, including mutations in EGFR, KRAS, HER2, BRAF, MET, and fusions affecting ALK, RET and ROS1, were also concurrently detected. The correlation between NF1 mutations and clinicomolecular features of patients was further evaluated. Among 704 patients, 42 NF1 mutations were found in 33 patients (33/704, 4.7%), including 14 patients harboring EGFR/NF1 comutations (14/33, 42.4%). Comparing with EGFR-mutant patients, patients harboring NF1 mutations were closely associated with solid component subtype (p = 0.028). Comparing with KRAS mutations, NF1 mutations were found more common in female and never smokers (p = 0.003 and p = 0.004, respectively). Kaplan-Meier survival analysis revealed that patients harboring NF1 mutation had similar disease-free survival (DFS) and overall survival (OS) with patients with KRAS mutation. Although frequently overlapped with EGFR mutation, patients harboring NF1 mutation had significantly shorter DFS (p = 0.019) and OS (p = 0.004) than patients with EGFR mutation. During follow-up, one female patient with EGFR exon 19 deletion and NF1 Q1815X comutation showed poor response to EGFR TKIs (Gefitinib and Osimertinib) after disease relapse. In conclusion, NF1 mutations define a unique molecular and clinicopathologic subtype of lung adenocarcinoma. Examination of NF1 mutation may contribute to molecular subtyping and therapeutic intervention of lung adenocarcinoma.

Vizcaino MA, Palsgrove DN, Yuan M, et al.
Granular cell astrocytoma: an aggressive IDH-wildtype diffuse glioma with molecular genetic features of primary glioblastoma.
Brain Pathol. 2019; 29(2):193-204 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Granular cell astrocytoma (GCA) is a rare adult infiltrating glioma subtype. We studied a series of 39 GCAs. Median age of presentation was 57.8 years and most cases developed in the frontal or temporal lobes. Tumors included grade II (n = 14), grade III (n = 11), and grade IV (n = 14) by WHO criteria. Granular cell morphology was diffuse in 31 (79%) cases and partial in eight (21%). Immunohistochemistry showed frequent positivity for GFAP (28 of 31), OLIG2 (16 of 16), and CD68 (27 of 30), but HAM56, CD163, and IBA-1 histiocytic markers were all negative (22 of 22). IDH1(R132H) was negative in all the cases tested (16 of 16), while ATRX expression was retained (12 of 12). Cytogenetics demonstrated monosomy 10 (6 of 6) cases, +7 in 4 (of 6), -13q in 4 of 6, and -14 in 4 of 6. Next-generation sequencing demonstrated mutations in PTEN/PIK3 genes in 6/13 (46%), NF1 in 3 of 10 (30%), TP53 in 3 of 13 (23%), PALB2 in 3 of 10 (30%), STAG2 in 3 of 10 (30%), EGFR mutation/amplification in 3 of 13 (23%), and AR in 2 of 10 (20%). CDKN2A/B deletion was identified in 5 of 13 (30%) cases (homozygous deletion in 4). The TERT C228T mutation was identified in 9 of 13 (69%). No mutations were encountered in IDH1, IDH2, CIC, FUBP1, H3F3A, BRAF or ATRX genes. The mean overall survival was 11.3 months. Patients >60 years old at diagnosis had a worse survival than patients <60 years (P = 0.001). There were no statistically significant differences in survival by WHO grade, extent of granular cell change, sex or MIB-1 (P > 0.05). GCA is a variant of IDH-wildtype diffuse glioma with aggressive behavior irrespective of grade and extent of granular cell morphology, and with molecular genetic features corresponding to primary glioblastoma.

Razavi P, Chang MT, Xu G, et al.
The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers.
Cancer Cell. 2018; 34(3):427-438.e6 [PubMed] Article available free on PMC after 10/09/2019 Related Publications
We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.

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