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PATH-46. DETECTING MISDIAGNOSED ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) BY DNA METHYLATION-BASED TUMOR CLASSIFICATION

ABSTRACT: Abstract Brain tumor diagnostics is achieved by combining morphology assessment and biomarker identification. However, the inter-observer variability of the histopathological diagnosis and lack of distinctive biomarkers makes these diagnoses particularly challenging. Recently, the potential for methylation-based characterization has been developed for brain tumors. To provide accurate and efficient brain tumor diagnostics, The Jackson Laboratory developed a DNA methylation array (Illumina Infinium HD Methylation EPIC), combining the “Classifier” established by the German Cancer Research Center (DKFZ), which can identify 82 distinct central nervous system tumors. Here we present a pediatric patient referred to us for medulloblastoma subtype classification by the methylation profile. Surprisingly, the array classified the tumor type as atypical teratoid/rhabdoid tumor (ATRT), subclass SHH. Also, the CNV profile indicated the SMARCB1/INI1 heterozygous deletion as part of the chromosome 22q deletion typically seen in ATRT, and absent was the isochromosome 17q commonly associated with medulloblastoma. Immunohistochemistry confirmed the loss of SMARCB1/INI1 expression leading to ATRT. Additionally, our NGS panel found a novel SMARCB1/INI1 frameshift variant c.1150delG (p.Ala384fs) in the last exon (exon 9). Although this variant is not expected to induce nonsense-mediated mRNA decay, it is located in the ATP-dependent nucleosome-remodeling complex domain Sfh1/SNF5 (IPR017393), which is associated with cell proliferation and differentiation. In addition, ClinVar reported several pathogenic/likely pathogenic variants in this domain, further supporting SMARCB1/INI1 c.1150delG which, together with the SMARCB1/INI1 deletion, may contribute to the loss of SMARCB1/INI1 expression, resulting in ATRT. We have identified the ATRT misclassification by the methylation profile and characterized a novel SMARCB1/INI1 variant c.1150delG most likely contributing to ATRT. We further propose that the DNA methylation profile will significantly improve the brain tumor diagnostics for cases with ambiguous, or contradictory histology and molecular profiles.

SUBMITTER: Hsiao M

PROVIDER: S-EPMC6847758 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract Novel therapies are needed to for the treatment of atypical teratoid/rhabdoid tumor (ATRT), an aggressive brain tumor that predominantly affects young children and has an average 5-year survival under 50%. Claudin-6 (CLDN6) is a tight junction protein present during development and is expressed in up to 70% of ATRT specimens but not in normal tissue, making it a promising immunotherapeutic target. CLDN6-targeted chimeric antigen receptor (CAR) T cells in combination with a CAR T cell-amplifying mRNA vaccine have demonstrated antitumor activity against other CLDN6-expressing cancers in pre-clinical and a phase I adult trial (NCT04503278; Haanen J et al AACR, 2022). To assess the effectiveness of CLDN6-targeted CAR T cells against ATRT, we utilized a second-generation mRNA CAR with a 4-1BB costimulatory domain and single-chain variable fragment against CLDN6 (Reinhard et al, 2020). CLDN6 expression in patient-derived ATRT specimens was profiled by RNAseq (mean FPKM 11.4) and immunohistochemistry (positive staining in 53% of specimens). Tumor-derived cell lines were assessed for CLDN6 expression by flow cytometry. Co-culture of CLDN6-directed mRNA CAR T cells resulted in tumor-specific cytotoxicity compared to CD19-directed control CAR T cells in CLDN6-positive ATRT cell lines 7316-2187 (92% versus 15% at 10:1, p < 0.0001; 86% versus 0% at 5:1, p<0.0001) and 7316-2141 (75% versus 7% at 10:1, p<0.0001; 53% versus 0% at 5:1, p< 0.0001). Patient-derived, orthotopic xenograft ATRT models were created through intracranial injection of tumor cells into the cerebellum of NSG mice. Following engraftment with 7316-2141, repeated intratumoral administration of mRNA CLDN6 CAR T cells resulted in significant tumor regression (-1.9x108 vs. +2.4x109 p/sec/cm2/sr, p<0.001) and improved survival compared to mRNA CD19 CAR T cells (median OS not reached vs. 13 days, p=0.002). This work highlights the potential for targeting CLDN6 via CAR T cell therapy in patients with ATRT as a novel therapeutic strategy.

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PATH-46. DETECTING MISDIAGNOSED ATYPICAL TERATOID/RHABDOID TUMOR (ATRT) BY DNA METHYLATION-BASED TUMOR CLASSIFICATION

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