Study of the Week: New Genetic Predisposition Variants in Rhabdomyosarcoma

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Germline cancer-predisposition variants in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group

We previously published about this research in a story titled “Research Identifies Genetic Precursors to Rhabdomyosarcoma,” which can be found here. The study was originally published in the medical journal Journal of the National Cancer Institute. You can view the abstract of it here.

What Happened?

Rhabdomyosarcoma in children has been previously connected to a number of syndromes associated with cancer-susceptibility. However, there hasn’t been more intensive research that has sought to dig deeper and identify some of the specific germline genetic variants that are directly linked to this rare and often lethal form of sarcoma. This is despite the fact that this is the most common form of soft tissue sarcoma in young children. The goal of this study was to conduct genetic sequencing in patients in order to “characterize the heterogeneous genetic etiologies of this often-fatal malignancy.”

The scientists conducting exome sequencing on a total of 615 patients that had recently been diagnosed with rhabdomyosarcoma. The findings from these tests then were compared with population controls. The researchers specifically focused on 63 autosomal-dominant cancer predisposition genes with the goal of comparing the prevalence of variants of these genes linked to cancer predisposition. Of the total number of patients tested, germline cancer predisposition variants were identified in 15 autosomal dominant genes in a total of 45 patients.

While this only constitutes 7.3 percent of all patients tested, this finding was still statistically significant when compared to the controls. Most of these variants (73.3 percent) were found in patients with previously identified genetic syndromes known to increase the risk of this cancer. These syndromes include neurofibromatosis type I (NF1 gene) and Li-Fraumeni syndrome (TP53 gene). Five patients were also identified with variants in the HRAS gene, which is associated with Costello syndrome

Germline variants were also found to be common in patients with embryonal rhabdomyosarcoma in comparison to the alveolar type. In addition, patients with germline predisposition variants tended to be younger when they were diagnosed; however, 40 percent of variants were identified in patients that were older than three years.

About Rhabdomyosarcoma (RMS)

Rhabdomyosarcoma is a type of soft tissue sarcoma cancer. It is highly aggressive and affects skeletal muscle cells that are not yet fully differentiated. Most people affected by the disease are under age 18. In many cases, the cause of rhabdomyosarcoma remains a mystery, and the cancer often appears sporadically. However, increased risk has been associated with certain genetic disorders and parental use of cocaine and marijuana may also increase the risk. The symptoms and presentation of this cancer vary widely and often depend on where the tumor appears; often a prominent lump is noticeable. This means that this cancer can, in some cases, be diagnosed early. Treatment approaches include surgery, chemotherapy, radiation, and immunotherapy. Outcomes vary substantially depending on location, but the cure rate for cancer that hasn’t spread is 75 percent. Relapsed or metastatic cancer has much worse survival rates. To learn more about rhabdomyosarcoma, click here.

Why Does it Matter?

These study results have significant implications for understanding the cause of this rare cancer as well as treatment. He Li, Ph.D., first author of this research, says:

“Currently, there are a limited number of genes considered to cause pediatric RMS…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.”

The researchers also concluded that genetic testing may be useful for a larger number of patients with rhabdomyosarcoma than was previously thought. Current practice recommends testing only for very young patients, but since the testing was able to reveal unexpected cancer susceptibility variants, particularly in patients greater than three years of age, this recommendation may need to be updated. After all, some of these variants may require more frequent monitoring of patients as they may increase the risk of other types of cancer appearing as the individual gets older.

Check back the Monday of each week for the next installment in this series.

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