A machine learning classifier trained on cancer transcriptomes detects NF1 inactivation signal in glioblastoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE85033 | GEO | 2017/02/01
SECONDARY ACCESSION(S): PRJNA335999
REPOSITORIES: GEO
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Project description:BACKGROUND:We have identified molecules that exhibit synthetic lethality in cells with loss of the neurofibromin 1 (NF1) tumor suppressor gene. However, recognizing tumors that have inactivation of the NF1 tumor suppressor function is challenging because the loss may occur via mechanisms that do not involve mutation of the genomic locus. Degradation of the NF1 protein, independent of NF1 mutation status, phenocopies inactivating mutations to drive tumors in human glioma cell lines. NF1 inactivation may alter the transcriptional landscape of a tumor and allow a machine learning classifier to detect which tumors will benefit from synthetic lethal molecules. RESULTS:We developed a strategy to predict tumors with low NF1 activity and hence tumors that may respond to treatments that target cells lacking NF1. Using RNAseq data from The Cancer Genome Atlas (TCGA), we trained an ensemble of 500 logistic regression classifiers that integrates mutation status with whole transcriptomes to predict NF1 inactivation in glioblastoma (GBM). On TCGA data, the classifier detected NF1 mutated tumors (test set area under the receiver operating characteristic curve (AUROC) mean?=?0.77, 95% quantile?=?0.53 - 0.95) over 50 random initializations. On RNA-Seq data transformed into the space of gene expression microarrays, this method produced a classifier with similar performance (test set AUROC mean?=?0.77, 95% quantile?=?0.53 - 0.96). We applied our ensemble classifier trained on the transformed TCGA data to a microarray validation set of 12 samples with matched RNA and NF1 protein-level measurements. The classifier's NF1 score was associated with NF1 protein concentration in these samples. CONCLUSIONS:We demonstrate that TCGA can be used to train accurate predictors of NF1 inactivation in GBM. The ensemble classifier performed well for samples with very high or very low NF1 protein concentrations but had mixed performance in samples with intermediate NF1 concentrations. Nevertheless, high-performing and validated predictors have the potential to be paired with targeted therapies and personalized medicine.
| S-EPMC5292791 | biostudies-literature
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays. We analyzed triceps muscles from 4 three-month-old wt controls and 4 three-month-old Nf1Prx1 mice using the Affymetrix Mouse Gene 1.0 ST platform. Array data was processed by the Affymetrix Exon Array Computational Tool. RNA isolated from each animal was hybridized to a separate microarray.
2011-05-18 | E-GEOD-29343 | biostudies-arrayexpress
Project description:Neurofibromatosis type 1 (NF1) is a multi-system disease caused by mutations in the NF1 gene encoding a Ras-GAP protein, neurofibromin, which negatively regulates Ras signalling. Besides neuroectodermal malformations and tumours, the skeletal system is often affected (e.g. scoliosis and long bone dysplasia), demonstrating the importance of neurofibromin for development and maintenance of the musculoskeletal system. Here we focus on the role of neurofibromin in skeletal muscle development. Nf1 gene inactivation in the early limb bud mesenchyme using Prx1-cre (Nf1Prx1) resulted in muscle dystrophy characterised by fibrosis, reduced number of muscle fibres, and reduced muscle force. To gain insight into the molecular changes of the observed muscle dystrophy and fibrosis and to compare these with other known muscle dystrophies, we performed transcriptional profiling of the entire triceps muscles of threemonth-old wild type (wt) and mutant animals using Affymetrix high-density microrrays.
2011-05-18 | GSE29343 | GEO
Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. 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. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.
2023-03-16 | GSE207512 | GEO
Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. 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. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.
2023-03-16 | GSE207513 | GEO
Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. 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. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.
2023-03-16 | GSE207514 | GEO
Project description:We performed whole genome SNP profiling on DNA samples from 236 patients with NF1, 123 with glimoa tumors and 113 without; 117 females and 119 males, together with 29 control samples. To identify polymorphisms in human adenylate cyclase 8 (AC8) which correlate with glioma risk in NF1 in a sex-specific manner, Ac8 SNP were extracted and further analyzed for their sex-specific NF1-associated glioma risk. Three SNPs on ADCY8 were found signficant while other SNPs on CXCR7 and ADCYAP1 were promising. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from blood samples or saliva samples in three separate sets with one processed in Washington University and two in University of Utah. The data included 29 control samples and 236 NF1 patient samples (123 with and 113 without GBM) with 153 blood specimen and 97 saliva specimen.
2015-02-20 | E-GEOD-62215 | 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: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:Background Neurofibromatosis type 1 (NF1) is a multi-organ disease caused by mutations in Neurofibromin (NF1). Amongst other features, NF1 patients frequently show reduced muscle mass and strength, impairing patients’ mobility and increasing the risk of fall. The role of Nf1 in muscle and the cause for the NF1-associated myopathy is mostly unknown. Methods To dissect the function of Nf1 in muscle, we created muscle-specific knockout mouse models for Nf1, inactivating Nf1 in the prenatal myogenic lineage either under the Lbx1 promoter or under the Myf5 promoter. Mice were analyzed during pre-and postnatal myogenesis and muscle growth. Results Nf1Lbx1 and Nf1Myf5 animals showed only mild defects in prenatal myogenesis. Nf1Lbx1 animals were perinatally lethal, while Nf1Myf5 animals survived up to approx. 25 weeks. Nf1Myf5 animals showed decreased postnatal growth, reduced muscle size, and fast fiber atrophy. Proteome and transcriptome analysis of muscle tissue indicated decreased protein synthesis and increased proteasomal degradation, and decreased glycolytic and increased oxidative activity in muscle tissue. Real-time respirometry demonstrated enhanced oxidative metabolism in Nf1Myf5 muscles concomitant to a fiber type shift from type 2B to type 2A and type 1. Nf1Myf5 muscles showed hallmarks of mild oxidative stress and increased activation of AMPK indicating an energy deficit, increased expression of atrogenes and decreased activation of mTORC1. Proteome and transcriptome analysis indicated that oxidative fibers mainly relied on fatty acid catabolism. Inline, Nf1Myf5 animals showed a drastic reduction of white, but not brown, adipose tissue. Conclusions Our results demonstrate a cell-autonomous role for Nf1 in myogenic cells during postnatal muscle growth required for metabolic and proteostatic homeostasis. Furthermore, Nf1 deficiency in muscle leads to cross-tissue communication and mobilization of lipid reserves.
2020-10-26 | PXD017958 | Pride