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| Open AccessKDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
There is lack of therapies targeting the PAX3-FOXO1 fusion oncogene in fusion-positive rhabdomyosarcoma (FP-RMS). Here, the authors identify and characterise an inhibitor with highest inhibition of histone lysine demethylase 3B that suppresses PAX3-FOXO1 activity in FP-RMS.
- Yong Yean Kim
- , Berkley E. Gryder
- & Javed Khan
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Article
| Open AccessProteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma
The molecular characterisation of soft tissue sarcomas (STSs) across diverse populations remains crucial. Here, the authors perform a proteomics and phosphoproteomics analysis of 272 Chinese STS patients across 12 subtypes, and obtain insights related to progression, metastasis, and immune signatures.
- Shaoshuai Tang
- , Yunzhi Wang
- & Chen Ding
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Article
| Open AccessASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97
VCP/p97 is identified as a co-factor to the fusion oncoprotein ASPSCR1::TFE3. They co-localize on chromatin, co-dependent for enhancer looping and transcriptional regulation in alveolar soft part sarcomas and Xp11- rearranged renal cell carcinomas.
- Amir Pozner
- , Li Li
- & Kevin B. Jones
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Article
| Open AccessDurvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial
Response rates to immune-checkpoint inhibitors in patients with advanced sarcoma remain modest. Here the authors report the results of a phase 2 study of durvalumab (anti-PD-L1) in combination with the anti-VEGF receptor tyrosine-kinase inhibitor pazopanib in unselected advanced sarcomas with correlative genomic analysis.
- Hee Jin Cho
- , Kum-Hee Yun
- & Hyo Song Kim
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Article
| Open AccessMulti-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions
The molecular characteristics and therapeutic vulnerabilities of TFCP2-rearranged rhabdomyosarcomas (RMS) require further exploration. Here, the authors use multi-omics analyses and functional and mechanistic investigations to characterize TFCP2-rearranged RMS – including cases with FUS/EWSR1-TFCP2 fusions – across two precision oncology programs.
- Julia Schöpf
- , Sebastian Uhrig
- & Claudia Scholl
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Article
| Open AccessPAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution
Different processes are in place to facilitate RNA-Polymerase 2 (Pol2) binding to chromatin. Here the authors reveal that the fusion transcription factor PAX3-FOXO1 shapes RNA Pol2 enhancer loops by recruitment of the histone acetyltransferase p300 via a small alpha-helical hook in its activation domain. Degradation of PAX3-FOXO1 or p300 rapidly collapses Pol2 clusters.
- Yaw Asante
- , Katharina Benischke
- & Marco Wachtel
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Article
| Open AccessComprehensive analysis reveals potential therapeutic targets and an integrated risk stratification model for solitary fibrous tumors
Solitary fibrous tumours are mesenchymal tumours with an unpredictable progression and current medical treatments for relapsed SFTs remain ineffective. Here, the authors identified potential therapeutic targets and risk factors for SFTs and created an integrated risk model using 101 patients, and validated in 3 independent cohorts to successfully predict tumour progression.
- Renjing Zhang
- , Yang Yang
- & Ziming Du
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Article
| Open AccessPAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors
Histologically, PAX3-FOXO1 (P3F) fusion-positive rhabdomyosarcoma (FP-RMS) resembles muscles cells, however, its cell-of-origin is less clear. Here, the authors demonstrate that P3F expression induces endothelial cells reprogramming into functional myogenic stem cells, driving the formation of FP-RMS in mouse models.
- Madeline B. Searcy
- , Randolph K. Larsen IV
- & Mark E. Hatley
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Article
| Open AccessSIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma
The tumour-specific functions of SIX1 homeoprotein in Ewing sarcoma (ES) remain poorly understood. Here, the authors suggest that SIX1, which enhances metastasis in most tumour types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes.
- Connor J. Hughes
- , Kaiah M. Fields
- & Heide L. Ford
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Article
| Open AccessThe proteomic landscape of soft tissue sarcomas
Characterising the molecular profile of soft tissue sarcomas (STS) remains critical. Here, the authors analyse samples from 321 STS patients across 11 histological subtypes using proteomics and identify prognostic signatures that can be applied to multiple subtypes.
- Jessica Burns
- , Christopher P. Wilding
- & Paul H. Huang
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Article
| Open AccessALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
Chimeric antigen receptor T (CAR-T) cells represent a breakthrough in the treatment of haematopoietic malignancies, however, in solid tumours this form of immune therapy is hampered by the scarcity of suitable targets showing high level tumour-restricted expression. Here authors generate CAR-T cells that target an osteosarcoma-specific isoform of alkaline phosphatase and show efficacy in orthotopic animal models while sparing healthy tissues.
- Nadia Mensali
- , Hakan Köksal
- & Sébastien Wälchli
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Article
| Open AccessMultiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities
Malignant peripheral nerve sheath tumours are an aggressive form of sarcoma, with limited treatment options. Here, the authors utilise DNA methylation and transcriptomic data to identify two subtypes of tumours with potential therapeutic vulnerabilities.
- Suganth Suppiah
- , Sheila Mansouri
- & Gelareh Zadeh
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Article
| Open AccessASPSCR1::TFE3 orchestrates the angiogenic program of alveolar soft part sarcoma
The mechanisms of angiogenesis in alveolar soft part sarcoma (ASPS) remain to be explored. Here, the authors highlight the role of the ASPSCR1::TFE3 fusion in regulating super-enhancer activity during the angiogenic process in ASPS.
- Miwa Tanaka
- , Surachada Chuaychob
- & Takuro Nakamura
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Article
| Open AccessGenomic characterization of DICER1-associated neoplasms uncovers molecular classes
DICER1 syndrome is associated with a predisposition to multiple tumor types. Here, the authors identify and characterize 3 molecular subgroups of mesenchymal tumors with DICER1 mutations.
- Felix K. F. Kommoss
- , Anne-Sophie Chong
- & William D. Foulkes
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Article
| Open AccesscircCsnk1g3- and circAnkib1-regulated interferon responses in sarcoma promote tumorigenesis by shaping the immune microenvironment
Circular RNAs can contribute to tumour progression. Here the authors show that two circular RNAs, circCsnk1g3 and circAnkib1 promote sarcoma growth by controlling the expression of interferon related genes and pro-inflammatory factors in sarcoma cells
- Roberta Piras
- , Emily Y. Ko
- & Jlenia Guarnerio
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Article
| Open AccessMulti-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment
Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.
- Yafei Jiang
- , Jinzeng Wang
- & Yingqi Hua
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Article
| Open AccessA phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors
In patients with progressive and symptomatic desmoid fibromatosis (DF) treatment with chemotherapy is typically prolonged, while surgery carries a high risk of relapse. Here, the authors report the results of a phase II clinical trial of short-course nab-paclitaxel in patients with progressive and symptomatic DF.
- Javier Martin-Broto
- , Andres Redondo
- & Nadia Hindi
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Article
| Open AccessBiomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou
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Article
| Open AccessTargeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus
Neither CDK4/6 inhibitors nor oncolytic adenoviruses show high efficiency as monotherapy in the treatment of cancer. Authors show here that when combined, CDK4/6 inhibitors deplete Retinoblastoma protein levels, which leads to more efficient virus replication and an increase in oncolytic virus-producing cancer cells and thus to efficient anti-tumor response in mouse xenograft sarcoma models.
- Jana Koch
- , Sebastian J. Schober
- & Per Sonne Holm
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Article
| Open AccessTherapeutic targeting of ATR in alveolar rhabdomyosarcoma
Alveolar rhabdomyosarcoma is a clinically challenging disease due to the lack of druggable targets. Here the authors show preclinical evidence for ATR inhibitors as a therapeutic option for alveolar rhabdomyosarcoma.
- Heathcliff Dorado García
- , Fabian Pusch
- & Anton G. Henssen
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Article
| Open AccessPilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma
The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.
- Sandra P. D’Angelo
- , Allison L. Richards
- & William D. Tap
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Article
| Open AccessClinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets
Sarcomas are rare tumours with many different subtypes and clinical outcomes; a broader knowledge of their genetic features is required. Here, the authors analyse 2138 soft tissue and bone sarcomas across 45 subtypes using MSK-IMPACT targeted sequencing and find genomic groups that are distinct from histological subgroups.
- Benjamin A. Nacev
- , Francisco Sanchez-Vega
- & William D. Tap
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Article
| Open AccessClinical genomic profiling in the management of patients with soft tissue and bone sarcoma
Comprehensive molecular profiles are required to understand and treat sarcomas, which comprise more than 70 different subtypes. Here, the authors profile the genomic landscape of 7494 sarcomas across 44 histologies using targeted panel sequencing and identify potential therapeutic targets.
- Mrinal M. Gounder
- , Narasimhan P. Agaram
- & Dexter X. Jin
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Article
| Open AccessThe androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma
Androgen receptor can promote tumour progression in desmoplastic small round cell tumour (DSRCT), an aggressive paediatric malignancy that predominantly affects young males. Here, the authors show that DSRCT is an AR-driven malignancy and sensitive to androgen deprivation therapy
- Salah-Eddine Lamhamedi-Cherradi
- , Mayinuer Maitituoheti
- & Joseph A. Ludwig
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Article
| Open AccessPhase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas
Oncoprotein SS18-SSX is a hallmark of synovial sarcoma. Here the authors report phase separation of SS18-SSX and the binding of SS18-SSX to chromatin remodeling complex are important for the transformation activity of the oncoprotein SS18-SSX.
- Yanli Cheng
- , Zhongtian Shen
- & Jiafu Long
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Article
| Open AccessHypoxia-activated neuropeptide Y/Y5 receptor/RhoA pathway triggers chromosomal instability and bone metastasis in Ewing sarcoma
Ewing sarcoma tumour cells frequently metastasize to the bone but the molecular mechanisms governing this process are not well understood. Here, the authors show that neuropeptide Y/Y5 receptor pathway is activated in the hypoxic tumour microenvironment, which results in cytokinesis defects and chromosomal instability, leading to bone invasion.
- Congyi Lu
- , Akanksha Mahajan
- & Joanna Kitlinska
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Article
| Open AccessEWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma
The relationship between cellular histogenesis and molecular phenotypes for the EWSR1- ATF1 fusion in clear cell sarcoma (CCS) requires further characterization. Here, the authors investigate the EWSR1-ATF1 gene regulation networks in CCS cell lines, primary tumors, and mesenchymal stem cells.
- Emely Möller
- , Viviane Praz
- & Nicolò Riggi
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Article
| Open AccessTherapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma
RB1 mutations are seen in 40-60% of sporadic osteosarcoma. Here, the authors demonstrate a selective sensitivity to PARP inhibitors in RB1-mutated osteosarcoma-derived cell lines that is not associated with canonical signatures indicative of a homologous recombination defect.
- Georgia Zoumpoulidou
- , Carlos Alvarez-Mendoza
- & Sibylle Mittnacht
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Article
| Open AccessSynthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity
PTEN copy number loss is found in 25% of fusion-negative rhabdomyosarcomas (FN-RMS). Here, the authors use a Hedgehog-driven FN-RMS mouse model to show that PTEN loss drives the expression of core transcription factor PAX7 and its transcriptional axis, which determines FN-RMS tumour identity.
- Casey G. Langdon
- , Katherine E. Gadek
- & Mark E. Hatley
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Article
| Open AccessLineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival
Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.
- Nathaniel D. Anderson
- , Yael Babichev
- & Adam Shlien
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Article
| Open AccessPromoter G-quadruplexes and transcription factors cooperate to shape the cell type-specific transcriptome
G-quadruplex (G4) structures play complex roles linked to transcription regulation. Here the authors, by comparing G4 location and transcript levels in liposarcoma and keratinocyte cells, reveal that G4s cooperate with transcription factors to determine cell-specific transcriptional programs.
- Sara Lago
- , Matteo Nadai
- & Sara N. Richter
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Article
| Open AccessSarcoma classification by DNA methylation profiling
Sarcomas are morphologically heterogeneous tumours rendering their classification challenging. Here the authors developed a classifier using DNA methylation data from several soft tissue and bone sarcoma subtypes, which has the potential to improve classification for research and clinical purposes.
- Christian Koelsche
- , Daniel Schrimpf
- & Andreas von Deimling
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Article
| Open AccessInteraction between SNAI2 and MYOD enhances oncogenesis and suppresses differentiation in Fusion Negative Rhabdomyosarcoma
Rhabdomyosarcomas are tumours blocked in myogenic differentiation, which despite the expression of master muscle regulatory factors, including MYOD, are unable to differentiate. Here, the authors show that SNAI2 is upregulated by MYOD through super enhancers, binds to MYOD target enhancers, and arrests differentiation.
- Silvia Pomella
- , Prethish Sreenivas
- & Myron S. Ignatius
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Article
| Open AccessSingle cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy
Promising results of cancer therapies in transplant tumor models often fail to predict efficacy in clinical trials. Here the authors show that, while transplant tumors are cured by radiotherapy and PD-1 blockade, autochthonous sarcomas are resistant to the identical treatment, recapitulating the immune landscape and resistance to checkpoint blockade observed in most sarcoma patients.
- Amy J. Wisdom
- , Yvonne M. Mowery
- & David G. Kirsch
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Article
| Open AccessSingle-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma
Osteosarcomas are difficult to treat and have a limited response to immunotherapy. Here, the authors analyse osteosarcomas at the single-cell level, and identify both the transdifferentiation of malignant cells and an array of immune cells that could have implications for metastasis and immunotherapy.
- Yan Zhou
- , Dong Yang
- & Haiyan Hu
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Article
| Open AccessA system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression
Chondrosarcomas are frequently aggressive, understanding the transcriptional changes associated with progression may help in developing new treatments. Here, the authors show that HIF-2α is increased in expression on progression and pharmacological inhibition of the protein together with chemotherapy is a useful strategy for controlling tumour growth in mice.
- Hyeonkyeong Kim
- , Yongsik Cho
- & Jin-Hong Kim
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Article
| Open AccessTumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma
Recurrent metastatic rhabdomyosarcoma remains largely incurable. Here, the authors describe a child with metastatic rhabdomyosarcoma who has durable response to HER2-specific CAR T cells and shows endogenous immune reactivity.
- Meenakshi Hegde
- , Sujith K. Joseph
- & Nabil Ahmed
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Article
| Open AccessOncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Ewing sarcoma is characterized by the fusion of EWSR1 and FLI1. Here, the authors show that EWSR1-FLI1 increases the activity of the developmental transcription factor SOX6, which promotes tumor growth but also increases sensitivity to oxidative stress.
- Aruna Marchetto
- , Shunya Ohmura
- & Thomas G. P. Grünewald
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Article
| Open AccessTargeting the CK1α/CBX4 axis for metastasis in osteosarcoma
Osteosarcoma is an aggressive tumour and little is known the mechanisms underpinning its highly metastatic nature. Here, the authors highlight a role for the CK1α/CBX4 axis in driving metastasis, suggesting that this pathway might be targeted for therapeutic benefit.
- Xin Wang
- , Ge Qin
- & Tiebang Kang
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Article
| Open AccessCASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG
Embryonal rhabdomyosarcoma (ERMS) is a childhood cancer with impaired myogenic differentiation despite the presence of myogenic transcription factors. Here, the authors show that CASZ1 directly regulates these myogenic factors and the loss of CASZ1 is due to RAS-MEK signaling in ERMS.
- Zhihui Liu
- , Xiyuan Zhang
- & Carol J. Thiele
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Article
| Open AccessTargeting glutamine metabolism slows soft tissue sarcoma growth
Glutamine is an energetic source required for the proliferation of cancer cells. Here, the authors show that soft tissue sarcomas expressing high levels of glutaminase (GLS) are particularly sensitive to glutamine starvation and GLS inhibition in tumour-bearing allograft and autochthonous mouse models.
- Pearl Lee
- , Dania Malik
- & M. Celeste Simon
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Article
| Open AccessIntegrated exome and RNA sequencing of dedifferentiated liposarcoma
Understanding the genomic features of dedifferentiated liposarcoma (DDLPS) is likely to uncover new options for management. Here, the authors reveal three prognostic groups, and highlight molecular markers associated with malignant transformation.
- Makoto Hirata
- , Naofumi Asano
- & Koichi Matsuda
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Article
| Open AccessIntegrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression
Chondrosarcomas are heterogenous tumours of the bone cartilage and have highly variable prognoses. Here, the authors perform a multi-omics analysis, revealing molecular features that can stratify clinical outcomes.
- Rémy Nicolle
- , Mira Ayadi
- & Gonzague de Pinieux
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Article
| Open AccessCooperation of cancer drivers with regulatory germline variants shapes clinical outcomes
Interactions between germline variants and somatic mutations is a relatively unexplored topic in cancer. Here, in Ewing sarcoma, the authors show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls MYBL2, whose high expression correlates with prognosis.
- Julian Musa
- , Florencia Cidre-Aranaz
- & Thomas G. P. Grünewald
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Article
| Open AccessBromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma
Liposarcoma (LPS) is a rare cancer that can acquire resistance to chemotherapy. Here, the authors map super-enhancers in LPS, finding BET-protein dependent mechanisms that can be targeted by a BET protein degrader, which also can overcome acquired resistance to chemotherapy in LPS.
- Ye Chen
- , Liang Xu
- & H. Phillip Koeffler
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Article
| Open AccessA serum microRNA classifier for the diagnosis of sarcomas of various histological subtypes
Sarcomas are rare malignant tumours of bone and soft tissue whose diagnosis remain difficult. Here, the authors analyse serum samples from over 1000 patients and using separate discovery, training and validation cohorts, identify and validate a 7-microRNA index that distinguishes malignant sarcomas from benign disease.
- Naofumi Asano
- , Juntaro Matsuzaki
- & Takahiro Ochiya
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Article
| Open AccessDifferent patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years
Hofvander and colleagues compare the patterns of clonal evolution in different pathogenetic subgroups of sarcoma. They show that sarcomas driven by gene fusion or amplification display few additional changes over time, whereas sarcomas with complex karyotypes show a gradual increase of nucleotide- and chromosome-level mutations.
- Jakob Hofvander
- , Björn Viklund
- & Fredrik Mertens
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Article
| Open AccessLoss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors
Granular cell tumors (GCTs) are rare tumors that arise in multiple anatomical locations. Here, the authors investigate the genomics of GCTs, finding inactivating somatic mutations in ATP6AP1 or ATP6AP2 in 72% of the 82 GCTs analyzed. In vitro manipulation of these genes recapitulated GCT phenotypes in cellular models.
- Fresia Pareja
- , Alissa H. Brandes
- & Jorge S. Reis-Filho
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Article
| Open AccessIntegrated genetic and epigenetic analysis of myxofibrosarcoma
Myxofibrosarcoma occurs in adults and is associated with high local relapse. Here, based on exome/transcriptome sequencing and DNA methylation analysis, the authors identify driver genes and methylation clusters associated with unique combinations of mutations, outcomes, and immune cell compositions.
- Koichi Ogura
- , Fumie Hosoda
- & Tatsuhiro Shibata