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Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1 deficient cases

ABSTRACT: Genome wide DNA methylation profiling of ATRTs and extracranial malignant rhabdoid tumors (eMRTs) samples harboring mutations in SMARCA4 and of small cell carcinoma of the ovary hypercalcemic type (SCCOHT) was performed . The Illumina Infinium HumanMethylation450 BeadChip and the Illumina Infinium MethylationEPIC arrays were used to obtain DNA methylation profiles across approximately 450,000 CpGs and 850,000 CpGs, respectively, in FFPE derived tumor samples. In total n=14 ATRT, n=6 eMRTs and n=28 SCCOHT samples were analyzed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161692 | GEO | 2020/12/18

REPOSITORIES: GEO

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Project description:Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant CNS neoplasm whichprimarily occurs in children under three years of age. Due to poor outcomes with intense and toxicmultimodality treatment, new therapies are urgently needed. Histone deacetylase inhibitors (HDIs)have been evaluated as novel agents for multiple malignancies and have been shown to function asradiosensitizers. They act as epigenetic modifiers and lead to re-expression of inappropriatelyrepressed genes, proteins, and cellular functions. Due to the underlying chromatin remodeling genemutation in ATRT, HDIs are ideal candidates for therapeutic evaluation. To evaluate the role of HDIsagainst ATRT in vitro, we assessed the effect of drug treatment on proliferation, apoptosis, and geneexpression. Additionally, we examined HDI pretreatment as a radiosensitization strategy for ATRT.MTS and clonogenic assays demonstrated that HDI treatment significantly reduces the proliferativecapacity of BT-12 and BT-16 ATRT cells. Also, the HDI SNDX-275 was able to induce apoptosis in bothcell lines and induced p21Waf1/Cip1 protein expression as measured by Western blot. Evaluation ofdifferential gene expression by microarray and pathway analysis after HDI treatment demonstratedalterations of several key ATRT cellular functions. Finally, we showed that HDI pretreatmenteffectively potentiates the effect of ionizing radiation on ATRT cells as measured by clonogenic assay.These findings suggest that the addition of HDIs to ATRT therapy may prove beneficial, especiallywhen administered in combination with current treatment modalities such as radiation. Keywords: ATRT; HDAC inhibitor; radiosensitization BT12 and BT16 cells were plated and subsequently treated for 24hr with IC25 concentrations of SNDX-275 (Sigma), at which time total RNA was collected. IC25 concentrations were calculated based on MTS assay.For BT12, the SNDX-275 IC25 was 1.4uM. For BT16, it was 0.44uM. The controls had DMSO added at equivalent volumes.

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Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1 deficient cases

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