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SMARCB1-deficient rhaboid tumors of the kidney and renal medullary carcinomas.

ABSTRACT: We used microarrays to compared gene expression profilings in various tumors of the kidney.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70421 | GEO | 2016/03/08

SECONDARY ACCESSION(S): PRJNA288603

REPOSITORIES: GEO

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SMARCB1-deficient rhaboid tumors of the kidney and renal medullary carcinomas.

Project description:We used microarrays to compared gene expression profilings in various tumors of the kidney. [human mRNA] 8 human RTK, 5 human RMC.

2016-03-08 | E-GEOD-70421 | biostudies-arrayexpress

Embryonic signature distinguishes pediatric and adult rhabdoid tumors from other SMARCB1-deficient cancers

Project description:We used microarrays to compare gene expression profilings in various SMARCB1-deficient tumors.

2017-08-13 | GSE94321 | GEO

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition.

Project description:Renal medullary carcinoma (RMC) is a rare and deadly kidney cancer in patients of African descent with sickle cell trait. We have developed faithful patient-derived RMC models and using whole-genome sequencing, we identified loss-of-function intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele. Biochemical and functional characterization of these models revealed that RMC requires the loss of SMARCB1 for survival. Through integration of RNAi and CRISPR-Cas9 loss-of-function genetic screens and a small-molecule screen, we found that the ubiquitin-proteasome system (UPS) was essential in RMC. Inhibition of the UPS caused a G2/M arrest due to constitutive accumulation of cyclin B1. These observations extend across cancers that harbor SMARCB1 loss, which also require expression of the E2 ubiquitin-conjugating enzyme, UBE2C. Our studies identify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which provides the foundation for a mechanism-informed clinical trial with proteasome inhibitors.

| S-EPMC6436895 | biostudies-literature

Mouse Smarcb1-deficient models recapitulate subtypes of human rhabdoid tumors.

Project description:Rhabdoid Tumors (RT) are highly aggressive tumors that are frequently localized in the central nervous system (CNS) where they are termed atypical teratoid and rhabdoid tumors (ATRT). We generated conditional Smarcb1-deficient mouse model leads to CNS Smarcb1-deficient tumors. We used microarrays to compared gene expression profilings of various human and mouse tumors. Our data demonstrate that the Smarcb1-deficient mouse model recapitulates the diversity of human RT.

2016-01-27 | GSE64019 | GEO

Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition

Project description:Whole gene expression arrays for primary and metastatic cell lines derived from patients with RMC

2019-03-26 | GSE111787 | GEO

Haplotype-resolved germline and somatic alterations in renal medullary carcinomas.

Project description:BackgroundRenal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited.MethodsWe used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus.ResultsWe find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events.ConclusionsOur findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.

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SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance.

Project description:Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.

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Genomics of pediatric renal medullary carcinomas

Project description:Genomics of pediatric renal medullary carcinomas

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Genomics of pediatric renal medullary carcinomas

Project description:Genomics of pediatric renal medullary carcinomas

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Embryonic signature distinguishes pediatric and adult rhabdoid tumors from other SMARCB1-deficient cancers.

Project description:Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of infancy, characterized by undifferentiated histological features and loss of SMARCB1 expression. The diagnosis is all the more challenging that other poorly differentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas (ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). Moreover, late cases occurring in adults are now increasingly reported, raising the question of differential diagnoses and emphasizing nosological issues. To address this issue, we have analyzed the expression profiles of a training set of 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, all < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n = 5). As compared with other SDT, RT are characterized by an embryonic signature, and up-regulation of key-actors of de novo DNA methylation processes. Using this signature, we then analysed the expression profiling of 37 SDT to infer the appropriate diagnosis. Thirteen adult onset tumors showed strong similarity with pediatric RT, in spite of older age; by exome sequencing, these tumors also showed genomic features indistinguishable from pediatric RT. In contrary, 8 tumors were reclassified within carcinoma, ES or UC categories, while the remaining could not be related to any of those entities. Our results demonstrate that embryonic signature is shared by all RT, whatever the age at diagnosis; they also illustrate that many adult-onset SDT of ambiguous histological diagnosis are clearly different from RT. Finally, our study paves the way for the routine use of expression-based signatures to give accurate diagnosis of SDT.

| S-EPMC5470964 | biostudies-literature

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