Affymetrix OncoScan CN analysis on breast cancer in women affected with Neurofibromatosis type 1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE115890 | GEO | 2018/07/20
REPOSITORIES: GEO
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Project description:Neurofibromatosis type 1 (NF1) is autosomal dominant condition caused by germline mutations in the NF1 gene on chromosome 17. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could result from the effect of NF1 mutation on microglia function. Using Nf1-mutant mice, we previously identified impaired microglia process extension and phagocytosis resulting from defects in purinergic signaling. To determine whether these abnormalities are also observed in human microglia, we leveraged human induced pluripotent stem cell engineering to generate human microglia-like (hiMGL) cells harboring three different NF1 patient-derived NF1 gene mutations. Both NF1-mutant and isogenic control hiMGL cells express classical microglial markers and exhibit similar transcriptomes and cytokine/chemokine release profiles, NF1-mutant hiMGL cells have defects in P2X receptor activation, phagocytosis and motility. We conclude that NF1 mutation impairs some aspects of microglia function in humans, which could contribute to a subset of the neurological abnormalities seen in children with NF1.
2023-12-14 | GSE203647 | GEO
Project description:We previously discovered a sex-by-genotype defect in microglia function using a germline heterozygous knockout mouse model of Neurofibromatosis type 1 (Nf1+/- mice), in which only microglia from male Nf1+/- mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1+/- microglia exhibit differences in protein expression, which largely reflect pathways involved cytoskeletal organization. In keeping with potential defects in cytoskeletal function, only male Nf1+/- microglia had reduced process arborization and surveillance capacity. Next, to determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG+/- mice). Surprisingly, neither male nor female Nf1MG+/- mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP+/- mice), the microglia defects found in Nf1+/- mice were recapitulated. Collectively, these data reveal that Nf1+/- sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.
2023-05-10 | PXD035881 | Pride
Project description:Affymetrix OncoScan CN analysis on breast cancer in women affected with Neurofibromatosis type 1
| PRJNA478150 | ENA
Project description:BACKGROUND: The NF1 tumor suppressor gene is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1) – a tumor predisposition syndrome caused by a germline NF1 mutation – have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanisms by which NF1 mutation leads to breast cancer tumorigenesis are not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. METHODS: To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development and develops highly penetrant breast cancer. RESULTS: We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient rat mammary mature adipocytes have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation but flow cytometry analysis did not show a change mammary adipose-derived mesenchymal stem cell abundance. CONCLUSION: Collectively, these studies uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary gland will create a foundation for developing early detection strategies of breast cancer among NF1 patients.
2023-05-08 | GSE231603 | GEO
Project description:Neurofibromatosis 1 (NF1) is a genetic, neurocutaneous syndrome caused by a mutation in the gene encoding neurofibromin. Individuals with NF1 develop growths that define the NF1 phenotype, including Lisch nodules, cafe-au-lait spots, and neurofibromas. However, more than 50% of individuals with NF1 have cognitive deficits, such as learning disorders and attention deficit/hyperactive disorder that are neuroanatomically unrelated to the neurofibromas. The purpose of this study is to determine the molecular basis of the neurodevelopmental changes that result from the primary gene mutation using a mouse model of NF. These mice are heterozygous for the Nf1 gene (NF+/-), and develop learning and memory difficulties that mimic humans, but do not develop tumors. By applying the technique of gene expression profiling to both NF+/- and control mice, we expect get a "genetic fingerprint" of 12,000 RNA molecules expressed in different parts of the brain during development. Comparison of the "genetic fingerprints" in these mice during development may help us identify key molecular changes that eventually result in cognitive deficits. Such an understanding of the molecular changes triggered by the primary gene mutation may eventually lead to treatments that prevent the cognitive deficits in NF1. Keywords: other
2004-06-17 | GSE1482 | GEO
Project description:Breast cancer is the most prevalent cancer in women, and most cases are believed to have a sporadic, rather than heritable basis. Therefore, a major challenge in cancer research is to determine the underlying genomic alterations leading to carcinogenesis and malignancy, and then use this information for personalized therapies. Genomic studies of human cancers that aim to identify causative mutations are complicated by the prevalence of passenger mutations, genetic heterogeneity, and the diversity of breast cancer etiologies and tumor subtypes. Mouse cancer models are powerful for untangling the genomic basis of cancers because genetic and phenotypic variation can be eliminated or controlled. To identify genes contributing to mammary tumorigenesis, we exploited the C3H-Mcm4Chaos3/Chaos3 (“Chaos3”) mouse model that, by virtue of bearing a defective DNA replicative helicase subunit that causes elevated genomic instability (GIN), sustains somatic alterations ultimately causing mammary adenocarcinomas. Genomic analysis of Chaos3 mammary tumors revealed recurrent copy number alterations (CNAs) of specific genomic regions, most notably deletion of the Neurofibromin 1 (Nf1) tumor suppressor gene in all cases. NF1, a negative regulator of RAS, is traditionally recognized for its role in driving the development of neurofibromas in the context of the human disease Neurofibromitosis but not breast cancer. We observed elevated RAS activation and increased sensitivity of both Chaos3 and human Nf1-mutated breast cancer lines to MAPK and/or PI3K/AKT pathway inhibitors. We also found striking overlap between Chaos3 CNAs and human breast cancer CNA data curated in public genomic databases, including Nf1 deletion. Together, our results indicate that spontaneous NF1 loss can drive breast cancer and suggests a potential therapeutic strategy in that subset of patients. reference x sample
2012-08-21 | E-GEOD-36240 | biostudies-arrayexpress
Project description:Breast cancer is the second most common cancer type worldwide, representing 25% of all cancers in women. PIK3CA is one of the most frequently mutated genes in breast cancer and mutations result in constitutive activation of the PI3K/mTOR pathway. More than 30 inhibitors against PI3K/mTOR are being tested in clinical trials, however, resistance mechanisms evolve frequently resulting in disease progression. The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. For this purpose, we used a genome-wide PiggyBac transposon mediated mutagenesis screen in a PIK3CAH1047R mutated murine tumor model. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. Additionally, we find that loss of NF1 correlates with enhanced glycolysis and lower levels of ROS. Unexpectedly, treatment with NAC sensitized NF1 KO cells to PI3K inhibition in vitro, and in vivo. Global phospho-proteomics indicated that the combination with NAC enhances the inhibitory effect of PI3K inhibition on mTOR signaling, which inhibits proliferation of NF1 KO tumor cells. This raises the interesting possibility to combine PI3K inhibition with NAC especially in NF1 loss tumors
2023-03-30 | PXD034644 | Pride
Project description:<p>Targeted genetic sequencing was performed on a 41-year-old female with metaplastic breast cancer (MBC) and neurofibromatosis type I (NF1). A custom panel capturing 279 cancer related genes was used to identify a germline pathogenic SNV in NF1, as well several other somatic alterations. </p>
| phs001566 | dbGaP
Project description:Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential NF1 mutation-specific effects on human central nervous system cells and tissues. While all mutations increased proliferation and RAS activity in two-dimensional (2D) neural progenitor cells (NPCs) and astrocytes, we observed striking NF1 mutation-specific effects on 2D NPC dopamine levels and NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate NF1 mutational specificity at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability.
2020-03-03 | GSE144601 | GEO
Project description:Affymetrix Oncoscan arrays were performed according to the manufacturer's directions on DNA extracted from FFPE-breast cancer tissues. Copy number analysis using Affymetrix Oncoscan arrays was performed for 29 primary breast cancers
2016-07-01 | E-GEOD-83916 | biostudies-arrayexpress