Integrated diagnosis based on transcriptome analysis in suspected pediatric sarcomas

AbstractPediatric solid tumors are a heterogeneous group of neoplasms with over 100 subtypes. Clinical and histopathological diagnosis remains challenging due to the overlapping morphological and immunohistochemical findings and the presence of atypical cases. To evaluate the potential utility of including RNA-sequencing (RNA-seq) in the diagnostic process, we performed RNA-seq in 47 patients with suspected pediatric sarcomas. Histopathologists specialized in pediatric cancer re-evaluated pathological specimens to reach a consensus diagnosis; 42 patients were diagnosed with known subtypes of solid tumors whereas 5 patients were diagnosed with undifferentiated sarcoma. RNA-seq analysis confirmed and refined consensus diagnoses and further identified diagnostic genetic variants in four of the five patients with undifferentiated sarcoma. Genetic lesions were detected in 23 patients, including the novel SMARCA4-THOP1 fusion gene and 22 conventional or recently reported genetic events. Unsupervised clustering analysis of the RNA-seq data identified a distinct cluster defined by the overexpression of rhabdomyosarcoma-associated genes including MYOG and CHRNG. These findings suggest that RNA-seq-based genetic analysis may aid in the diagnosis of suspected pediatric sarcomas, which would be useful for the development of stratified treatment strategies.

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Faculty Opinions recommendation of Preclinical evaluation of the PARP inhibitor, olaparib, in combination with cytotoxic chemotherapy in pediatric solid tumors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718110185.793522091 ◽

2016 ◽

Author(s):

Stephen Lessnick

Keyword(s):

Solid Tumors ◽

Parp Inhibitor ◽

Cytotoxic Chemotherapy ◽

Preclinical Evaluation ◽

Pediatric Solid Tumors

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Immunometabolism: A ‘Hot’ Switch for ‘Cold’ Pediatric Solid Tumors

Trends in Cancer ◽

10.1016/j.trecan.2021.05.002 ◽

2021 ◽

Author(s):

Lin Xiao ◽

Harrison Yeung ◽

Michelle Haber ◽

Murray D. Norris ◽

Klaartje Somers

Keyword(s):

Solid Tumors ◽

Pediatric Solid Tumors

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PATH-17. INTRAGENIC COPY NUMBER BREAKPOINT ANALYSIS OF METHYLATION DATA FROM CNS TUMOURS IDENTIFIES NOVEL SUBGROUP-SPECIFIC CANDIDATE FUSION GENE ENRICHMENTS

Neuro-Oncology ◽

10.1093/neuonc/noaa222.652 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii427-iii428

Author(s):

Alan Mackay ◽

Yura Grabovska ◽

Matthew Clarke ◽

Diana Carvalho ◽

Sara Temelso ◽

...

Keyword(s):

Copy Number ◽

Fusion Gene ◽

High Grade Glioma ◽

Structural Variations ◽

Methylation Array ◽

Kinase Gene ◽

Integrated Diagnosis ◽

Cns Tumours ◽

Breakpoint Analysis ◽

Balanced Translocations

Abstract Methylation array-based molecular profiling has redefined the classification of brain tumours and now forms an important part of their integrated diagnosis, providing both subgroup assignment and genome wide DNA copy number profiles. These latter data can be used to identify intragenic breakpoints which are frequently associated with structural variations resulting in therapeutically targetable oncogenic fusion genes. To systematically assess the landscape of these alterations, we combined publicly available methylation datasets resulting in a total of 5660 CNS tumours, around half paediatric, and including >1000 high grade glioma and DIPG. These were analysed by standard methodology (MNP, conumee), and intragenic breakpoint enrichment was compared within methylation subgroups, superfamilies, and tumours with no high-scoring classification. Benchmarking included sequence-verified cases such as infant hemispheric gliomas (IHG) with ALK(15%) and ROS1(7%) fusions, and pathognomic alterations associated with specific entities such as RELA-EPN, MYB-LGG and HGNET-MN1. We identified previously unreported enrichments of well-recognised fusion targets such as NTRK2in GBM_MID and NTRK3in DMG_K27 (both 5%), METin A_IDH / A_IDH_HG (3–5%), and FGFR1/3in GBM_G34 (8–9%). Novel recurrent kinase gene candidates to be verified and explored further include IGF1Rin 2–12% cases spanning glioma subgroups, and TIE1in poorly classified tumours. This latter ‘NOS’ group were also enriched in various transcription factor targets of breakpoints, including TCF4and PLAGL2. Despite limitations due to sample quality, resolution or balanced translocations, breakpoint analysis of methylation copy number profiles provides simple screening for structural rearrangements which may directly influence targeted therapy in paediatric CNS tumours.

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Approaches to Enhance Natural Killer Cell-Based Immunotherapy for Pediatric Solid Tumors

Cancers ◽

10.3390/cancers13112796 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2796

Author(s):

Aicha E. Quamine ◽

Mallery R. Olsen ◽

Monica M. Cho ◽

Christian M. Capitini

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Solid Tumors ◽

Nk Cell ◽

Therapeutic Option ◽

Treatment Options ◽

Intensive Therapy ◽

Killer Cell ◽

Cell Therapies ◽

Pediatric Solid Tumors

Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

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