Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

Abstract

Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery.

Transcriptomic Subtyping of Malignant Peripheral Nerve Sheath Tumours Highlights Immune Signatures, Genomic Profiles, Patient Survival and Therapeutic Targets

“…Our study also validated the importance of previously identified target genes on chromosome arm 17q in MPNST, including BIRC5, TK1, and TOP2A. 22,23,68,82,83 We have previously suggested that high expression levels of these genes and their encoded proteins represent a prognostic risk profile among patients with MPNST. 20 In conclusion, we report an integrative molecular study of MPNSTs at the genomic and transcriptomic levels.…”

Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets

“…Nonetheless, the comparisons of MPNST subtypes and neurofibromas supported a previous meta-analysis showing upregulation of genes related to DNA replication and cell cycle pathways in MPNSTs relative to benign tumours, as well as downregulation of genes relevant for peripheral nervous system development and immune complement activation. 68 Our study further suggested that downregulation of immune activity was specific to the immune deficient subtype, but it is not known whether this is consistent in comparison with atypical neurofibromas. Downregulation of differentiation markers such as SOX10 was found in the least aggressive subtype of MPNSTs relative to neurofibromas, and this has also been shown in a comparison of MPNSTs with normal Schwann cells, supporting appropriateness of the neurofibromas as a non-malignant reference.…”

“…Our study also validated the importance of previously identified target genes on chromosome arm 17q in MPNST, including BIRC5, TK1, and TOP2A . 22 , 23 , 68 , 82 , 83 We have previously suggested that high expression levels of these genes and their encoded proteins represent a prognostic risk profile among patients with MPNST. 20 …”

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency

“…TOP2A, one of the top 20 genes upregulated in MPNST [41], encodes the enzyme DNA topoisomerase II alpha, which controls and alters the topologic states of DNA during transcription. Matching this observation, PNF1 tumor cell lines displayed drug-resistance to anthracycline topoisomerase inhibitors, e.g., idarubicin, epirubicin, mitoxantrone, and doxorubicin.…”