Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.
McMaster PLUS Selected
This article has been identified as especially clinically relevant or newsworthy by at least 3
practicing clinicians and of high scientific quality by expert researchers
as a part of the McMaster PLUS article rating service.
BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma.
METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m(2) on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m(2) on days 1 and 8 and intravenous docetaxel 75 mg/m(2) on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry.
FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment.
INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma.
FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.
Oncology (7) Sarcoma (9), Neutropenia (4), Neoplasms (4), more mentions
Abstract: Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy in oropharyngeal squamouscellcarcinoma (OPSCC) that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. After applying standard critical appraisal policy and endorsement procedures, ASCO chose to endorse the ASTRO guideline.
Oncology (6) Squamous Cell Carcinoma (2), Neoplasms (2), more mentions
AbstractText: Nonmelanomaskincancers (NMSCs) of the ear are considered high risk... chart review of 649 consecutive patients treated with MMS at Mayo Clinic for primary cutaneous basalcellcarcinomas (BCCs) or squamouscellcarcinomas (SCCs) of the ear AbstractText: Nineteen percent of consecutively referred patients had NMSC of the ...
AbstractText: Protective effects of UV-B radiation against nonmelanomaskincancer (NMSC) are exerted via signaling mechanisms involving the vitamin D ... who received a diagnosis of and were being treated for basalcellcarcinoma or squamouscellcarcinoma (cases) and 100 individuals who were receiving treatment of a condition other than skincancer (controls) at the dermatology clinics at the Kirklin Clinic of ...
... tested the association between plasma 25(OH)D levels and non-melanomaskincancer observationally, and between genetically determined 25(OH)D levels and non-melanomaskincancer through an instrumental variable approach.Multivariable adjusted hazard ratios of non-melanomaskincancer were 3.27 (95%CI: 2.22;4.84) for plasma 25(OH ...
Imiquimod 5% topical cream is approved for treatment of superficial basalcellcarcinoma (BCC. Data on the long-term efficacy and usage in other BCC subtypes are scarce.Evaluation of long-term safety and efficacy of topical imiquimod treatment in various BCC subtypes and locations, with individualized treatment duration.Histopathologically confirmed BCCs treated solely with topical imiquimod were identified retrospectively ...
Detecting basalcellcarcinomas (BCCs) early and at relatively small sizes may expand therapeutic choices and enable less invasive treatment options. To this end, dermoscopy is a useful tool to diagnose BCC at early stages with high sensitivity and specificity.(1) Superficial BCCs have been shown to be independently associated with location on the trunk and extremities and nodular BCCs ...