Dataset Information

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

ABSTRACT: Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

SUBMITTER: Holdhof D

PROVIDER: S-EPMC7847432 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Holdhof Dörthe D Johann Pascal D PD Spohn Michael M Bockmayr Michael M Safaei Sepehr S Joshi Piyush P Masliah-Planchon Julien J Ho Ben B Andrianteranagna Mamy M Bourdeaut Franck F Huang Annie A Kool Marcel M Upadhyaya Santhosh A SA Bendel Anne E AE Indenbirken Daniela D Foulkes William D WD Bush Jonathan W JW Creytens David D Kordes Uwe U Frühwald Michael C MC Hasselblatt Martin M Schüller Ulrich U

Acta neuropathologica 20201217 2

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct m ...[more]

PMID: 33331994

Similar Datasets

Project description:Loss of function in SMARCB1/INI1 has been observed in a group of malignancies collectively defined as SMARCB1/INI1-deficient neoplasms. Primary intracranial SMARCB1/INI1-deficient tumors in adults are extremely rare. We collected eight primary adult sellar SMARCB1/INI1-deficient tumors to study their clinicopathological and (epi)genetic characteristics. We performed a comprehensive assessment of the clinical, radiological, morphological and immunohistochemical features. FISH analysis for the SMARCB1 locus and target exome sequencing for 425 cancer relevant genes were performed. Furthermore, six bona fide proximal epithelioid sarcoma (PES), fourteen atypical teratoid/rhabdoid tumors (ATRT) in brain and five pediatric poorly differentiated chordomas (PDC) in the clivus were collected for comparative analysis of differential diagnostic maker expression and DNA methylation profile. The median age was 47.1 years, ranging from 26 to 73 years. On morphology, tumors were characterized by sheets of monomorphic larger epithelioid-like cells, in two cases with rhabdoid cells. "Stag-horn" vasculatures were observed in five cases. The loss of INI1 protein expression, co-expression of epithelial makers and mesenchymal markers were observed in all cases. CD34 expression was observed in six cases. Heterozygous deletion of SMARCB1/INI1 was confirmed using FISH in six cases. The results of target exome sequencing showed three patients harbored heterozygous point mutations in SMARCB1. The epigenetic features of the primary adult sellar SMARCB1/INI1-deficient tumors resembled the ATRT-MYC subgroup, but clustered apart from PES and PDC. Based on epigenetic characteristics, primary adult sellar SMARCB1/INI1-deficient tumors represent a subtype of ATRT with similar epigenetic characteristics of ATRT-MYC subgroup. Our findings suggest that DNA methylation profiling should be utilized for differential diagnosis for the majority of epithelioid sarcoma and (sellar) rhabdoid tumor.

Project description:BACKGROUND: To describe therapeutic approaches in children with atypical Teratoid Rhabdoid Tumours (ATRT) in France. METHODS: Observational study including all children less than 18 years old diagnosed with ATRT in France between 2009 and 2011. RESULTS: Forty seven children were included in this retrospective study. Six patients received no curative treatment while forty-one patients had a curative project. Median age was 1.5 years (range 0-16). The disease was disseminated in 10 patients. Surgical resection was complete in 21 cases. Chemotherapy was administered in 41 children. Twenty-six patients received upfront Vincristine-Methotrexate (5g/m2 x 3) with intra-thecal Methotrexate, which was stopped in eleven patients: in four cases the disease progressed and in seven cases the toxicities were manageable. Fifteen children received different chemotherapy courses and in four of them the diseases progressed. Eight patients underwent second-look surgery. Radiotherapy was administered in 17 patients at a median time of 19 weeks (13-44) after diagnosis. High-dose chemotherapy (HDCT) was given in 9 children and maintenance therapy in 5 children, starting at respectively 35 and 42 weeks after diagnosis. Median follow-up was 26 months (0.6-47). Median time for progression was 5 months. Two-years overall survival was 32% + /-8%. Median survival was 8 months. DISCUSSION: The survival rate of children with ATRT remains poor, the addition of VM is easily manageable but its benefit remains uncertain. The disease progressed mostly before radiotherapy. Future trials should focus on the delay of radiotherapy and the benefit of HDCT. Because ATRT is a rare disease of infancy carrying grim prognosis, focus on long term outcome, especially neurocognitive remain very limited. With the new era of multimodality therapy, some patients are now long term survivors. We reviewed the neuropsychological (NP) status of the survivors from the Canadian ATRT registry. Among patients diagnosed between 1995-2012, 16/72 were survivors (22%). Formal NP assessments were available in 7 patients. Four patients could not be tested (3 too young, 1 blind significantly impaired, 1 lost to follow up). Additionally 1 patient was in special education class (grade 12), one received educational assistance (grade 8), one meet academic expectation (grade 4). Data on last survivor is pending. For the 7 patients with comprehensive NP, the median age at diagnosis was 28.2 months (11.2-60.7). Four tumors were infratentorial and 3 were metastatic. Four patients underwent complete resection. All patients received post operative sequential high dose chemotherapy (Carpoplatin/Thiotepa). Five patients received intrathecal chemotherapy. Two patients underwent radiation (1focal, 1CSI). Median age at time of NP was 7.3 years (3.9-9.28). Full Scale Intellectual Quotient (FSIQ) ranged from 60 to 119 (median = 71). Simple expressive and receptive language appeared relatively preserved (low average to superior). Three most recently diagnosed patients assessed at a median time of 2.6 years (2.6-4.7) from diagnosis had average to high average scores for FSIQ, academic and visual spatial skills, visual and verbal memory. Four other diagnosed earlier tested at a median time of 5.1 years (3.3-8.3) post-diagnosis had a FSIQ ranging from 60 to 71 (median = 68). Approximately 50% of their scores were in the impaired range. Whether these findings suggest further decline overtime or reflect improvement in overall management of these recently diagnosed patients remain unclear. Nevertheless this cohort of infants appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognition are definitely needed before embracing adjuvant radiotherapy as standard of care.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets