Genetic Precursors to Pediatric Rhabdomyosarcoma Identified


“But our study is pointing to new genes to consider. For example, we found that the BRCA2 gene, typically associated with adult breast and ovarian cancer, may also somehow influence the susceptibility of pediatric RMS.”

Germline predisposition variants associated with cancer susceptibility syndromes can underlie the genetic risk for rhabdomyosarcoma (RMS), indicating that germline testing should be performed in accordance with RMS subtypes and irrespective of age, according to findings from a study published in the Journal of the National Cancer Institute.1,2

Germline cancer-predisposition variants were identified in 45 patients with RMS across 15 autosomal dominant genes (7.3%; all FOXO1 fusion—negative). The enrichment of germline cancer-predisposition variants in this population was statistically significant compared with controls (1.4%; P = 1.3 x 10-22). The majority of the predisposition variants (73.3%) were identified in predisposition genes that have been linked to pediatric RMS risk, such as TP53 (Li-Fraumeni syndrome), NF1 (neurofibromatosis type I), HRAS, and BRCA2.

“Currently, there are a limited number of genes considered to cause pediatric RMS,” said He (Hurley) Li, PhD, postdoctoral associate at the Human Genome Sequencing Center at Baylor College of Medicine and first author of the study. “But our study is pointing to new genes to consider. For example, we found that the BRCA2 gene, typically associated with adult breast and ovarian cancer, may also somehow influence the susceptibility of pediatric RMS.”

“Our study highlights the utility of sequencing large numbers of children diagnosed with cancer to identify these types of changes, termed pathogenic variants,” said Philip Lupo, PhD, associate professor of pediatrics, hematology and oncology at Baylor College of Medicine, and corresponding author of the study. “Understanding the frequency of these variants in children with RMS could influence strategies for genetic testing and future surveillance of patients with a pathogenic variant, as some of these variants may predispose children to multiple cancers later in life.”

RMS is an aggressive tumor and the most common soft tissue sarcoma in children. Despite its prevalence, the genetic susceptibility of the malignancy is not as well defined compared with other pediatric malignancies.

Germline DNA from 615 patients with newly diagnosed RMS, consented through the Children’s Oncology Group, underwent whole-exome sequencing. The prevalence of cancer-predisposition variants in 63 autosomal dominant cancer-predisposition genes in these patients was compared with population controls (n = 9963).

Additional findings showed that 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) linked to Costello syndrome.

Differences in genetic etiology were reported based on histology. Specifically, germline variants were more common in patients with embryonal versus alveolar RMS (10.0% vs 3.0%, respectively; P = .02).

Furthermore, patients with a cancer-predisposition variant were found to be younger at diagnosis (P = 9.9 x 10-4), and approximately half of germline variants (40.0%) were identified in patients aged 3 years or older, contrasting current genetic testing guidelines in patients diagnosed at an early age.

“These results may change our current decisions about when to offer genetic testing for children with RMS, which right now is focused on very young patients,” concluded Sharon Plon, MD, PhD, medical geneticist on the study team and professor of pediatrics, oncology and molecular and human genetics at Baylor College of Medicine.


Li H, Sisoudiya SD, Martin-Giacalone BA, et al. Germline cancer-predisposition variants in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. JNCI. 2020. doi:10.1093/jnci/djaa204

Genomic assessment of cancer-predisposition landscape of pediatric rhabdomyosarcoma. News release. Baylor College of Medicine. December 30, 2020. Accessed January 4, 2021.

This article was originally published on OncLive as, "TP53, NF1 Among Genetic Variants Identified as Precursors to Pediatric Rhabdomyosarcoma."

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