Genomic Characteristics of Pediatric Rhabdomyosarcoma Tumors

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In an analysis from an international consortium reported in the Journal of Clinical Oncology, Shern et al identified genomic characteristics and associated outcomes in pediatric rhabdomyosarcoma. Among the findings were that MYOD1 and TP53 mutations were associated with poorer outcomes.

As stated by the investigators, “Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are available for risk stratification.”

Study Details

The dataset from the internal consortium (Children’s Oncology Group [COG], Children’s Cancer and Leukaemia Group, Young Onset Sarcoma Subgroup, National Cancer Institute) included data on a total of 641 patients enrolled in COG trials from 1998 to 2017 (COG cohort, n = 344) and UK patients enrolled in malignant mesenchymal tumor and RMS2005 trials from 1995 to 2016 (UK cohort, n = 297).

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Key Findings

Among the 641 patients, a median of one mutation (range = 0–5) was found per tumor.

Among 515 FOXO1 fusion–negative (FN) patients, mutation of any RAS pathway member was found in > 50% of cases and no putative driver mutation was identified in 21%. The most common RAS isoform mutations were NRAS (17%), KRAS (9%), and HRAS (8%). Mutations in the tumor-suppressor genes BCOR (15%), NF1 (15%), and TP53 (13%) were found at a higher incidence than previously reported. Mutations in

Among 126 FOXO1 fusion–positive (FP) patients, the most common alterations were focal amplification of CDK4 (13%) or MYCN (10%), with alterations in BCOR (6%), NF1 (4%), TP53 (4%), and PIK3CA (2%) found in a smaller proportion of cases.

RAS isoforms predominated in FN infants aged < 1 year, being found in 64% of cases, including HRAS mutation in 40%.

TP53 mutations were associated with worse outcomes in both FP and FN cases. All 5 FP patients (3 in COG and 2 in UK cohorts) with a TP53 mutation had a fatal outcome. Among FN cases, presence of TP53 mutation was associated with poorer event-free survival on univariate analysis (hazard ratio [HR] = 2.07, P = .0083) and risk-stratified analysis (HR = 1.97, P = .0146) in the COG cohort and in univariate (HR = 2.01, P = .0079) and risk-stratified analysis (HR = 2.11, P = .0055) in the UK cohort.

MYOD1 mutation was found in no FP patients and in 17 (3%) FN cases. MYOD1 mutations were associated with previously unidentified histologic patterns beyond spindle histology, older age, head and neck primary site, and poor outcomes. Among FN cases, MYOD1 mutations were associated with poorer event-free survival in univariate (HR = 6.84, P < .0001) and risk-stratified analysis (HR = 5.58, P < .001) in the COG cohort and in univariate (HR = 3.32, P =.0133) and risk-stratified analysis (HR = 3.46, P = .0111) in the UK cohort.

The investigators have provided a searchable companion database (, containing all genomic variants and clinical annotation, including survival data.

The investigators stated, “This study nominates mutant genes MYOD1 and TP53 as indicators of poor prognosis in fusion-negative rhabdomyosarcoma, and TP53 alterations as a biomarker of more aggressive disease in fusion-positive disease. Mutation of MYOD1 was not restricted to spindle histology, and the association with adverse outcome highlights the need to accurately diagnose MYOD1 mutations and develop novel treatment strategies for these patients.”

They concluded, “This is the largest genomic characterization of clinically annotated rhabdomyosarcoma tumors to date and provides prognostic genetic features that refine risk stratification and will be incorporated into prospective trials.”

Jack F. Shern, MD, of the Pediatric Oncology Branch, National Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the St. Baldrick’s Hero Fund, National Cancer Institute, Chris Lucas Trust, Talan’s Trust, Alice’s Arc charity, and Cancer Research UK. For full disclosures of the study authors, visit

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