Genomic assessment of cancer-predisposition landscape of pediatric rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is a highly malignant tumor and the most common soft tissue sarcoma in children. In spite of its clinical significance, less is known about genetic susceptibility to this malignancy compared to other pediatric cancers. Researchers at Baylor College of Medicine led the largest genomic assessment of children with RMS to determine the prevalence of genetic changes that result in cancer predisposition. The results are published in the Journal of the National Cancer Institute.
The study included 615 patients with newly diagnosed RMS from Children’s Oncology Group institutions across North America. Researchers at Texas Children’s Cancer Center, the Dan L Duncan Comprehensive Cancer Center and the Human Genome Sequencing Center at Baylor analyzed whole-exome sequencing data from inherited DNA of these patients to determine the prevalence of clinically significant variants in cancer-predisposition genes compared to a control group of nearly 10,000 individuals. The results showed that 7.3% of patients with RMS had clinically significant variant changes in cancer-predisposition genes compared to 1.4% of controls.
“Our study highlights the utility of sequencing large numbers of children diagnosed with cancer to identify these types of changes, termed pathogenic variants,” said Dr. Philip Lupo, associate professor of pediatrics – hematology and oncology at Baylor 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.”
Identifying cancer predisposition variants
Researchers also sought to identify if cancer-predisposition variants varied by tumor subtype—embryonal or alveolar—and patient age. In tumor subtype analysis, the team found that patients with embryonal RMS were significantly more likely to have cancer-predisposition variants than patients with alveolar RMS (10% vs. 3%). Also, while younger children were more likely to have cancer-predisposition variants, these findings were not limited to patients 3 years of age and younger as previously expected.
“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,” said Dr. Sharon Plon, medical geneticist on the study team and professor of pediatrics – oncology and molecular and human genetics at Baylor.
In terms of specific genes, analyses showed variants in genes previously reported as being important for RMS, including TP53, NF1, and HRAS. However, there also were notable findings in other genes, including BRCA2, which was found more often in the RMS patients compared to the controls.
“Currently, there are a limited number of genes considered to cause pediatric RMS,” said Dr. He Li, postdoctoral associate at the Human Genome Sequencing Center at Baylor 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.”
Expanding the analysis
Next, the researchers want to move their analysis beyond the list of known cancer-predisposition genes. The team recently received funding from the National Institutes of Health to perform whole-genome sequencing on inherited and tumor DNA from a larger patient cohort.
“The 7.3% prevalence rate we found is probably the lower boundary,” said Dr. Aniko Sabo, assistant professor at the Human Genome Sequencing Center at Baylor and senior author of the study. “We only focused on a specific list of cancer-predisposition genes. We haven’t looked genome wide or at structural variants yet. That means there is probably much more to be learned in relation to genetic predisposition to RMS.”
The team also hopes this work will lead to further research examining whether these pathogenic variants may impact patient outcomes, including response to therapy, likelihood of relapse, and overall survival.
“RMS is a tumor for which we have not seen a lot of improvement in available therapies over the last 30 years compared to other pediatric tumors,” said Lupo, a member of the Dan L Duncan Comprehensive Cancer Center at Baylor and director of the childhood cancer epidemiology and prevention program at Texas Children’s Hospital. “We need these large-scale studies and collaborations to move the needle when it comes to improving outcomes for these children.”
Other study authors include Saumya D. Sisoudiya, Bailey A. Martin-Giacalone, Michael M. Khayat, Shannon Dugan-Perez, Deborah A. Marquez-Do, Dr. Michael E. Scheurer, Donna Muzny, Dr. Eric Boerwinkle, Dr. Richard Gibbs, Dr. Yueh-Yun Chi, Dr. Donald A. Barkauskas, Tammy Lo, David Hall, Dr. Douglas R. Stewart, Dr. Joshua D. Schiffman, Dr. Stephen X. Skapek and Dr. Douglas S. Hawkins. They are affiliated with the following institutions: Baylor College of Medicine, Texas Children’s Hospital, the University of Texas Health Science Center at Houston, Children's Hospital Los Angeles, University of Southern California, Children’s Oncology Group, National Cancer Institute, University of Utah, the University of Texas Southwestern Medical Center and Seattle Children’s Hospital.
This work was supported by the Cancer Prevention and Research Institute of Texas (grant RP170071). For a complete list of funding sources, see the publication.