Genetic susceptibility in children, adolescents, and young adults diagnosed with soft-tissue sarcomas

Würtemberger, Julia; Ripperger, Tim; Vokuhl, Christian; Bauer, Sebastian; Lüttichau, Irene Teichert-von; Wardelmann, Eva; Niemeyer, Charlotte M.; Kratz, Christian P.; Schlegelberger, Brigitte; Hettmer, Simone

doi:10.1016/j.ejmg.2023.104718

Cited by 6 publications

(7 citation statements)

References 171 publications

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“…recently conducted a large systematic review and meta‐analysis to assess the contribution of germline pathogenic variants in genes involved in DNA repair in cancer risk in children and adolescents 48 . An additional review reported on genetic susceptibility in patients with soft tissue sarcomas diagnosed at all ages 49 . These two reviews included studies that reported on RMS of all subtypes and confirmed our sources of large‐scale germline sequencing programs that informed this set of results.…”

Section: Discussionmentioning

confidence: 81%

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A systematic review of the prevalence of pathogenic or likely pathogenic germline variants in individuals with FOXO1 fusion‐positive rhabdomyosarcoma

Freycon,

Lupo,

Witkowski

et al. 2023

Pediatric Blood & Cancer

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Several cancer predisposition syndromes (CPS) are reported to predispose to rhabdomyosarcoma, most frequently in children with embryonal rhabdomyosarcoma. There are lingering questions over the role of CPS in individuals with alveolar rhabdomyosarcoma (ARMS), which are frequently driven by FOXO1 fusion oncoproteins. We conducted a systematic review to identify patients with FOXO1 fusion‐positive ARMS (FP‐ARMS) who underwent germline DNA sequencing. We estimated the prevalence of pathogenic/likely pathogenic (P/LP) variants in cancer predisposing genes (CPGs) and of CPSs. We included 19 publications reporting on 191 patients with FP‐ARMS. P/LP variants in CPGs were identified in 26/191 (13.6%) patients, nine (4.9%) of which were associated with a CPS diagnosis. Evidence for causal associations between CPSs and FP‐ARMS could not be assessed with available data from this review. Only one patient was affected with a CPS known to predispose to rhabdomyosarcoma, Li–Fraumeni syndrome. Typical CPS associations with rhabdomyosarcoma are rare, but not nonexistent, in patients with FP‐ARMS. FOXO1 fusion status, alone, is insufficient for clinicians to rely on to distinguish between patients with/without CPS.

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Section: Discussionmentioning

confidence: 81%

“…48 An additional review reported on genetic susceptibility in patients with soft tissue sarcomas diagnosed at all ages. 49 These two reviews included studies that reported on RMS of all subtypes and confirmed our sources of large-scale germline sequencing programs that informed this set of results.…”

Section: Nb Patients With Arms and Fusion Positivementioning

confidence: 80%

A systematic review of the prevalence of pathogenic or likely pathogenic germline variants in individuals with FOXO1 fusion‐positive rhabdomyosarcoma

Freycon,

Lupo,

Witkowski

et al. 2023

Pediatric Blood & Cancer

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“…Pathogenic/likely pathogenic (P/LP) germline variants in cancer predisposition genes were detected in 7-17% of children, adolescents and young adults with RMS who were included in published germline sequencing cohorts [75][76][77][78][79]. Specific RMS phenotypes [80] were linked to P/LP variants in certain cancer predisposition genes, such as P/LP TP53 germline variants (anaplastic histology, [81]) and P/LP DICER1 germline variants (location of primary tumors in the female urogenital tract, [82]). The most frequent P/LP germline variants associated with young-onset RMS were TP53, NF1, and BRCA2 [75][76][77][78][79].…”

Section: Genetic Rms Susceptibility Due To Pathogenic Germline Varian...mentioning

confidence: 99%

“…We note that childhood cancer risk in BRCA1/2 germline variant carriers has been deemed negligible. In-depth studies, including parallel tumor/germline sequencing, are necessary to further explore the possible causal relationship between the development of RMS (including associated phenotypes and disease risk) and BRCA2 and other germline variants [80].…”

Section: Genetic Rms Susceptibility Due To Pathogenic Germline Varian...mentioning

confidence: 99%

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Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Pomella

Danielli

Alaggio

et al. 2023

Cancers

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Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.

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Advancing rare cancer research by MALDI mass spectrometry imaging: Applications, challenges, and future perspectives in sarcoma

Stillger,

Li,

Hönscheid

et al. 2024

Proteomics

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MALDI mass spectrometry imaging (MALDI imaging) uniquely advances cancer research, by measuring spatial distribution of endogenous and exogenous molecules directly from tissue sections. These molecular maps provide valuable insights into basic and translational cancer research, including tumor biology, tumor microenvironment, biomarker identification, drug treatment, and patient stratification. Despite its advantages, MALDI imaging is underutilized in studying rare cancers. Sarcomas, a group of malignant mesenchymal tumors, pose unique challenges in medical research due to their complex heterogeneity and low incidence, resulting in understudied subtypes with suboptimal management and outcomes.In this review, we explore the applicability of MALDI imaging in sarcoma research, showcasing its value in understanding this highly heterogeneous and challenging rare cancer. We summarize all MALDI imaging studies in sarcoma to date, highlight their impact on key research fields, including molecular signatures, cancer heterogeneity, and drug studies. We address specific challenges encountered when employing MALDI imaging for sarcomas, and propose solutions, such as using formalin‐fixed paraffin‐embedded tissues, and multiplexed experiments, and considerations for multi‐site studies and digital data sharing practices.Through this review, we aim to spark collaboration between MALDI imaging researchers and clinical colleagues, to deploy the unique capabilities of MALDI imaging in the context of sarcoma.

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Genetic susceptibility in children, adolescents, and young adults diagnosed with soft-tissue sarcomas

Cited by 6 publications

References 171 publications

A systematic review of the prevalence of pathogenic or likely pathogenic germline variants in individuals with FOXO1 fusion‐positive rhabdomyosarcoma

A systematic review of the prevalence of pathogenic or likely pathogenic germline variants in individuals with FOXO1 fusion‐positive rhabdomyosarcoma

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Advancing rare cancer research by MALDI mass spectrometry imaging: Applications, challenges, and future perspectives in sarcoma

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