Rhabdomyosarcoma: How Advanced Molecular Methods Are Shaping the Diagnostic and Therapeutic Paradigm

Abstract

For the past 40 years, progress in rhabdomyosarcoma (RMS) has been focused on understanding its molecular basis and characterizing the mutations that drive its tumorigenesis and progression. Genetic predisposition to RMS has allowed discovery of key genetic pathways and driver mutations. Subclassification of RMS into embryonal (ERMS) and alveolar (ARMS) subtypes has shifted from histology to PAX-FOXO1 fusion status, and new driver mutations have been found in spindle cell RMS. Comprehensive molecular profiling leveraging genome-scale next-generation sequencing (NGS) indicates that the RAS/RAF/PI3K axis is mutated in the majority of ERMS and modulated by downstream effects of PAX-FOXO1 fusions in ARMS. Because of the continued poor outcome of high-risk RMS, a variety of molecular targets have been or are now being tested in current or recent therapy trials. New techniques such as single cell sequencing, spatial multi-omics, and CRISPR/Cas9 genome editing offer potential for further discovery, but a need for clinically annotated specimens persists.

The Impact of Expert Pathology Review and Molecular Diagnostics on the Management of Sarcoma Patients: A Prospective Study of the Hellenic Group of Sarcomas and Rare Cancers

“…This is probably explained by the relatively small sample size and the histotypes that were included. The diagnostic value of molecular methods has been demonstrated for certain histotypes, including synovial sarcoma [37], rhabdomyosarcoma [10,38], clear cell sarcoma [39], and desmoid tumors [40]. The numbers of these histotypes, as well as GIST (n = 2), are underrepresented in our cohort.…”

Clinicopathologic characteristics, treatment, prognosis and pregnancy outcomes in rhabdomyosarcoma of the uterine cervix: a case series

“…The aetiology of cervical RMS is currently unclear. Recent studies have found that RMS, especially ERMS, is more common in children with certain genetic syndromes [5]. These patients often have multiple primary cancers, and a possible correlation between ERMS, especially cervical ERMS, and DICER1 pathogenic variants has been found [6][7][8].…”

“…These patients often have multiple primary cancers, and a possible correlation between ERMS, especially cervical ERMS, and DICER1 pathogenic variants has been found [6][7][8]. PAX-FOXO1 fusions are present in approximately 80% of ARMS, and missense mutations in MYOD1 are the most common molecular alterations in adult spindle cell/sclerosing RMS [5].…”

Fore-arm rhabdomyosarcoma in neurofibromatosis type 1: A unique case

“…Beckwith-Wiedemann syndrome, Gorlin syndrome, Costello syndrome, Noonan syndrome, and neurofibromatosis type I. 2,4 RMS has two major subcategories: alveolar and embryonic. Alveolar RMS has a distinct alveolar architecture, with tumor cells nestled between collagenous septa.…”