Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene

Abstract

Understanding the biological pathways critical for common neurofibromatosis type 1 (NF1) peripheral nerve tumours is essential, as there is a lack of tumour biomarkers, prognostic factors and therapeutics. We used gene expression profiling to define transcriptional changes between primary normal Schwann cells (n = 10), NF1-derived primary benign neurofibroma Schwann cells (NFSCs) (n = 22), malignant peripheral nerve sheath tumour (MPNST) cell lines (n = 13), benign neurofibromas (NF) (n = 26) and MPNST (n = 6). Dermal and plexiform NFs were indistinguishable. A prominent theme in the analysis was aberrant differentiation. NFs repressed gene programs normally active in Schwann cell precursors and immature Schwann cells. MPNST signatures strongly differed; genes up-regulated in sarcomas were significantly enriched for genes activated in neural crest cells. We validated the differential expression of 82 genes including the neural crest transcription factor SOX9 and SOX9 predicted targets. SOX9 immunoreactivity was robust in NF and MPSNT tissue sections and targeting SOX9 – strongly expressed in NF1-related tumours – caused MPNST cell death. SOX9 is a biomarker of NF and MPNST, and possibly a therapeutic target in NF1.

Plasma S100β is not a useful biomarker for tumor burden in neurofibromatosis

“…To date, no reliable circulating biomarkers have been validated for nerve sheath tumors although adrenomedullin, MIA, and SOX9 have been suggested for future Page 8 development [9][10][11]. Proteomic analysis of plasma samples from NF and non-NF patients may help identify candidate proteins that correlate with tumor burden.…”

Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

“…9 To identify differentially expressed genes between plexiform neurofibromas and malignant peripheral nerve sheath tumors, surrogate variables were extracted with sva. Then, for each gene, we constructed a linear fixed effects model: yBm þ TumorType þ e, where y is the residual following sva, m is the expected expression level, TumorType is the effect of tumor type and e is the residual error.…”

“…[3][4][5][6] A number of miRNAs, cell cycle regulators, signaling molecules and transcription factors have been shown to be differentially expressed between neurofibromas and malignant peripheral nerve sheath tumors including CDKN2A, TP53, RB1, EGFR, CD44, PDGFRB, PDGFRA, HGF, MET, IGFR1, SOX9, SOX10, miR-34a and miR-21. 3,[7][8][9][10][11][12][13][14] Neurofibromatosis type 1 patients often have multiple plexiform neurofibromas. Their risk of developing a malignant peripheral nerve sheath tumor is estimated to be in the range from 3-13%.…”

“…A few studies have performed cDNA microarray analysis to identify expression signatures of malignant peripheral nerve sheath tumor. 9,10,12,19 These studies have used frozen tissue or cell lines derived from tumors. They showed differences in the gene expression pattern between neurofibromas and unmatched malignant peripheral nerve sheath tumor samples from other patients.…”

Role of LRF/Pokemon in lineage fate decisions

“…[91][92][93][94][95][96] Accordingly, for instance, downregulation of LRF in primary advanced prostate cancer accompanied by heterozygous genetic loss of the LRF gene in castration-resistant metastatic advanced prostate cancer have been recently described in subgroups of patients and directly linked to tumor progression and androgen deprivation resistance (G.W. et al, manuscript submitted December 2012; A.L.…”