RESUMEN
In this Letter, the sentence beginning "This work was funded ." in the Acknowledgements should have read "CPRIT (RP140105) to J.C.R." rather than "CPRIT (RP150445) to J.C.R." This error has been corrected online.
RESUMEN
Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress. In addition, homologous recombination is impaired in Ewing sarcoma owing to an enriched interaction between BRCA1 and the elongating transcription machinery. Finally, we uncover a role for EWSR1 in the transcriptional response to damage, suppressing R-loops and promoting homologous recombination. Our findings improve the current understanding of EWSR1 function, elucidate the mechanistic basis of the sensitivity of Ewing sarcoma to chemotherapy (including PARP1 inhibitors) and highlight a class of BRCA-deficient-like tumours.
Asunto(s)
Proteína BRCA1/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Conformación de Ácido Nucleico , Proteínas de Fusión Oncogénica/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Proteína EWS de Unión a ARN/metabolismo , Reparación del ADN por Recombinación , Sarcoma de Ewing/genética , Transcripción Genética , Proteína BRCA1/metabolismo , Línea Celular Tumoral , Daño del ADN , Humanos , Proteínas de Fusión Oncogénica/genética , Proteína Proto-Oncogénica c-fli-1/genética , Proteína EWS de Unión a ARN/genética , Sarcoma de Ewing/metabolismoRESUMEN
Sixteen years since their initial description in the literature, posterior mediastinal Mullerian cysts - otherwise known as cysts of Hattori, after their discoverer - remain rare, with only 40 patients reported as of 2020. We report a 43 year old obese female that presented with a 2.6â cm cyst found in the posterior mediastinum by endoscopic ultrasound (EUS) and previously by chest magnetic resonance imaging (MRI) originally diagnosed as a congenital enteric duplication cyst of the esophagus radiologically. Upon surgical excision via a DaVinci thoracoscopy, the cyst was confirmed to be of Mullerian origin by PAX8, WT1, and ER staining. It is possible that the majority of cysts of Hattori remain unrecognized and undiagnosed, given their rarity and resemblance to other pathologies. It is important that this entity become a part of every pathologist's differential for a posterior mediastinal cyst in a female.