Pioneer factors in development and cancer DOI Creative Commons
Benjamin D. Sunkel, Benjamin Z. Stanton

iScience, Journal Year: 2021, Volume and Issue: 24(10), P. 103132 - 103132

Published: Sept. 15, 2021

Transcription factors (TFs) are essential mediators of epigenetic regulation and modifiers penetrance. Studies from the past decades have revealed a sub-class TF that is capable remodeling closed chromatin states through targeting nucleosomal motifs. This pioneer factor (PF) class remodeler ATP independent in its roles initiation, with nucleosome-motif recognition association repressive regions. Increasing evidence suggests fundamental properties PFs can be coopted human cancers. We explore role larger context tissue-specific regulation. Moreover, we highlight an emerging chimeric PF derived translocation partners disease associated rare tumors. In age site-directed genome editing targeted protein degradation, increasing our understanding will provide access to next-generation therapy for driven altered transcriptional circuitry.

Language: Английский

Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute–Children's Oncology Group Pediatric MATCH Trial DOI
D. Williams Parsons, Katherine A. Janeway, David R. Patton

et al.

Journal of Clinical Oncology, Journal Year: 2022, Volume and Issue: 40(20), P. 2224 - 2234

Published: March 30, 2022

The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts childhood and young adult patients with cancer by screening tumors for actionable alterations.

Language: Английский

Citations

95
An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children's Oncology Group clinical trials DOI
Josephine H. HaDuong, Christine M. Heske, Wendy Allen‐Rhoades

et al.

Pediatric Blood & Cancer, Journal Year: 2022, Volume and Issue: 69(4)

Published: Feb. 7, 2022

Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population variable overall survival rates ranging between approximately 6% 100% depending on defined risk factors. Although the stratification of patients has been refined across five decades collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes evolution current stratification, defines new incorporating novel biomarkers, provides rationale for upcoming Children's Oncology Group RMS studies.

Language: Английский

Citations

76
Evolving classification of rhabdomyosarcoma DOI
Narasimhan P. Agaram

Histopathology, Journal Year: 2021, Volume and Issue: 80(1), P. 98 - 108

Published: Dec. 27, 2021

Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents United States, occurring 4.5 million people aged below 20 years. Based on clinicopathological features genetic abnormalities identified, rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell/sclerosing pleomorphic subtypes. Each subtype shows distinctive morphology has characteristic abnormalities. This review discusses evolution classification rhabdomyosarcoma to present day, together with a discussion key histomorphological each diagnostic approach these tumours.

Language: Английский

Citations

104
Phase II Study of Selumetinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Genetic Alterations: Arm E of the NCI-COG Pediatric MATCH Trial DOI
Olive S. Eckstein, Carl E. Allen, P. Mickey Williams

et al.

Journal of Clinical Oncology, Journal Year: 2022, Volume and Issue: 40(20), P. 2235 - 2245

Published: April 1, 2022

The NCI-COG Pediatric MATCH trial assigns patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II studies of molecularly targeted therapies on the basis detection predefined genetic alterations. Patients tumors harboring mutations fusions driving activation mitogen-activated protein kinase (MAPK) pathway were treated MEK inhibitor selumetinib.

Language: Английский

Citations

53
Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe DOI Creative Commons
Simone Hettmer, Corinne M. Linardic, Anna Kelsey

et al.

European Journal of Cancer, Journal Year: 2022, Volume and Issue: 172, P. 367 - 386

Published: July 12, 2022

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence 1–2/million. Inter/intra-tumour heterogeneity raise challenges clinical, pathological and biological research studies. Risk stratification European North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status place alveolar histology. International working groups propose a coordinated approach through INternational Soft Tissue SaRcoma ConsorTium to evaluate specific genetic abnormalities generate integrate molecular data related patients RMS across different trial settings. We review relevant present consensus view what features should be assessed. In particular, we recommend assessment MYOD1-LR122R mutation for risk escalation, as it has been associated poor outcomes spindle/sclerosing rare classic embryonal histopathology. The prospective analyses fusion genes beyond PAX3/7-FOXO1 will new linked TP53 mutations CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants other cancer predisposition also DNA/RNA profiling tumours at diagnosis/relapse serial plasma samples is recommended where possible validate potential biomarkers, identify biomarkers assess how liquid biopsy can have greatest benefit. Together development molecularly-derived therapeutic strategies that review, synchronised international expected enhance progress towards improved treatment assignment, management RMS.

Language: Английский

Citations

43
Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma DOI
Yun Wei, Qian Qin, Chuan Yan

et al.

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(8), P. 961 - 975

Published: Aug. 18, 2022

Language: Английский

Citations

40
Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance DOI Creative Commons
Sara G. Danielli, Ermelinda Porpiglia, Andrea J. De Micheli

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(6)

Published: Feb. 8, 2023

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, high-content imaging resolve intratumoral heterogeneity patient-derived primary RMS cultures. We show that the aggressive alveolar (aRMS) subtype contains plastic muscle stem-like cells cycling progenitors drive tumor growth, subpopulation differentiated lost its proliferative potential correlates better outcomes. While chemotherapy eliminates progenitors, it enriches aRMS for cells. screened drugs hijacking toward clinically favorable subpopulations identified combination RAF MEK inhibitors potently induces myogenic differentiation inhibits growth. Overall, our work provides insights into states underlying aggressiveness, chemoresistance, progression identifies RAS pathway as promising therapeutic target.

Language: Английский

Citations

34
FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma DOI
Henry de Traux de Wardin, Joanna Cyrta, Josephine K. Dermawan

et al.

Genes Chromosomes and Cancer, Journal Year: 2024, Volume and Issue: 63(4)

Published: April 1, 2024

The wide application of RNA sequencing in clinical practice has allowed the discovery novel fusion genes, which have contributed to a refined molecular classification rhabdomyosarcoma (RMS). Most fusions RMS result aberrant transcription factors, such as PAX3/7::FOXO1 alveolar (ARMS) and involving VGLL2 or NCOA2 infantile spindle cell RMS. However, recurrent driving oncogenic kinase activation not been reported Triggered by an index case unclassified (overlapping features between ARMS sclerosing RMS) with FGFR1::ANK1 fusion, we reviewed our files for cases harboring FGFR1-related fusions. One additional FGFR1::TACC1 was identified tumor resembling embryonal (ERMS) anaplasia, but no pathogenic variants TP53 DICER1 on germline testing. Both occurred males, aged 7 24, pelvis. 2nd also harbored alterations, including somatic TET2 mutations. Two (one unclassified, one ERMS) FGFR1 overexpression lacking were sequencing. These two FGFR1::TACC1-positive clustered together ERMS group RNAseq. This is first report it remains unclear if define subset alternatively, whether this alteration can sporadically drive pathogenesis known subtypes, ERMS. Additional larger series integrated genomic epigenetic datasets are needed better subclassification, resulting underscores potential targeted therapy.

Language: Английский

Citations

9
Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma DOI Creative Commons
Sara G. Danielli, Yun Wei, Michael A. Dyer

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 26, 2024

Abstract Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity shared with human development has not been described. Using single-cell/nucleus RNA sequencing from patient tumors, patient-derived xenografts, primary in vitro cultures, and lines, we identify four dominant muscle-lineage states: progenitor, proliferative, differentiated, ground cells. We stratify these RMS cells/nuclei along continuum of show they share expression patterns fetal/embryonal myogenic precursors rather than postnatal satellite Fusion-negative (FN-RMS) have discrete stem hierarchy recapitulates fetal contain therapy-resistant FN-RMS progenitors transcriptomic similarity bipotent skeletal mesenchymal Fusion-positive tumor-acquired cells states, including neuronal state, are found development. This work identifies previously underappreciated unique treatment-resistant states differ across subtypes.

Language: Английский

Citations

9
Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes DOI
Michael T. Meister, Marian J.A. Groot Koerkamp,

Terezinha de Souza

et al.

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(10)

Published: Aug. 2, 2022

Language: Английский

Citations

38