Atypical Teratoid Rhabdoid Tumor are aggressive pediatric malignancies characterized by biallelic inactivation of a single gene; SMARCB1 a core subunit of the hSWI/SNF chromatin remodelling complex regulating hundreds of downstream genes/pathways. We performed RNA-seq/ Methylation profiling on primary Rhabdoid Tumors (RT) and a panel of RT cell lines re-expressing SMARCB1 to identify and characterise the molecular profiles of primary RT subtypes and downstream SMARCB1-dependent pathways that may be critical to RT tumorigenesis. We identified by integrated network-based pathway analysis key genes/pathways which are deregulated at the transcriptional/methylation level and are characteristic of primary RT or particular RT subtypes but also SMARCB1-dependent in our functional models. These SMARCB1-dependent pathways were further validated by quantitative proteomic analysis (LC-MS/MS) performed in our RT model and protein abundance cross-referenced with RNA-seq to give insight into the similarities in regulation at both proteomic and transcriptomic level and drug-targeting opportunities in RT. SMARCB1-dependent gene/pathway deregulation was verified and validated by targeted pathway manipulation and quantified by qRT-PCR and phenotypic changes. Key pathways/genes include but are not limited to E2F1, AURKA, BMI1, PLK1, SHH, Rho, TGF-Beta, PDGFRa, FGFR1, Wnt and STAT3/IL-6. PDGFRa, FGFR1, STAT3/IL-6 and Wnt mechanisms were further investigated in vitro using available inhibitors. Rhabdoid cells showed sensitivity to pathway inhibition and cell death by dysregulation of several downstream SMARCB1-dependent oncogenes. Integrative analysis of -omics data allows us to collate a detailed catalogue of the effect of SMARCB1 loss within RT subtypes revealing key regulators/effectors among differentially expressed and methylated genes that may ultimately be targetable therapeutically.

An 8-year-old girl presented with multiple, asymptomatic skin lesions localized to her right lower abdomen. These had first appeared 6 years previously, and had gradually increased in number over the intervening years. The patient was otherwise systemically well. On physical examination, a plaque 50 mm in size was found on the patient's right abdomen, made up of coalescing, firm, red-brown papules and nodules ranging from 4 to 10 mm in size (Fig. 1).Laboratory investigations gave normal results for full blood count, urea and electrolytes, liver function tests and protein electrophoresis. However, autoantibody screen revealed a positive titre of anti-smooth muscle antibodies (anti-SMA) (≥ 1 : 320); the rest of the autoantibody screen was negative. Histopathological findingsA punch biopsy was taken from one of the lesions, and histological examination revealed an unencapsulated dermal proliferation comprising of bland spindleshaped cells associated with collagen and scattered histiocytes (Fig. 2). Occasional foci of rounding off of collagen were noted at the periphery of the lesion. There was irregular acanthosis of the epidermis, with no increase in basal pigmentation or trichoblastic induction. The spindle-shaped cells stained positively for Factor XIIIa and negatively for CD34, SMA, desmin, CD99 and S-100P. CD34 and SMA highlighted the stroma around the proliferation and the blood vessels.What is your diagnosis? DiagnosisMultiple clustered dermatofibromas (MCDF).