Scientists Identify How Gene Mutation Drives a Deadly Childhood Cancer

Illustration of girl standing in front of charging bull

This image, inspired by "Fearless Girl" and "Charging Bull," aims to represent how understanding gene fusions is important in fighting cancers that affect children and young adults. The "HA" designates a molecular tag added to the fusion protein. Image by Cecilia Banito and Pedro Lourenço.

Researchers at the Sloan Kettering Institute have unraveled how a genetic mutation drives a type of aggressive soft tissue cancer called synovial sarcoma. This often-deadly cancer primarily affects children and young adults. It rarely responds to chemotherapy.

Using patient-derived cancer cell lines and the genome-editing tool CRISPR, the team of scientists led by molecular biologist Scott Lowe showed how the protein product of this mutation wreaks havoc: It hijacks molecules that normally turn genes off during development, turning them on instead.

“It’s an insidious mechanism that the oncogene uses to drive the cancer,” Dr. Lowe says. “But it also points us to potential treatment approaches.”

The genetic mutation at the root of synovial sarcoma causes two separate genes from different chromosomes to become spliced together. The conjoined genes produce a novel “fusion” protein called SS18-SSX1/2. This fusion mutation is found in nearly all of synovial sarcoma tumors and is often the only genetic mutation identified. That suggests it plays a role as the primary driver of the cancer.

Dr. Lowe and his team, including postdoctoral fellow Ana Banito, showed that the fusion protein interferes with the way that nearby genes are packaged in chromatin, leading them to be turned on in error. One of the molecules involved is known as KDM2B, which normally silences genes during development. When it is targeted by the fusion protein, it leads to gene activation and, ultimately, to cancer.

Green blob on black background

Human synovial sarcoma cells containing the fluorescently tagged fusion protein.

Now that researchers know how the mutation leads to cancer, they can try to develop therapies that stop its effects and restore the normal gene expression pattern. Such potentially reversible patterns of altered gene expression are sometimes called epigenetic, since they don’t require changing the DNA sequence of genes. In fact, the authors showed that inhibiting KDM2B function can block synovial sarcoma growth.

Dr. Banito notes that the methods they applied in this study, including using the CRISPR/Cas9 system to tag a fusion protein in patient-derived cell lines, could be used to understand how other oncogenic gene fusions work. Addressing the action of such fusion proteins in childhood cancers is one of the ten major goals of the Blue Ribbon Panel for the Cancer Moonshot initiative, she says.

A paper describing these results was published today in the journal Cancer Cell.

Katelyn’s Story
Learn how Katelyn overcame a rare form of sarcoma at Memorial Sloan Kettering.

This work was supported by the National Institutes of Health, the Liddy Shriver Sarcoma Initiative, the Canadian Cancer Society Research Institute, the Terry Fox Research Institute, the Christina Renna Foundation, the Clark Gillies Foundation, the Friends of T.J. Foundation, and the Michelle Paternoster Foundation for Sarcoma Research. Dr. Lowe is the Geoffrey Beene Chair for Cancer Biology and an investigator at the Howard Hughes Medical Institute. Dr. Banito is now with the Hopp Children’s Cancer Center at the NCT Heidelberg (KITZ), German Cancer Research Center (DKFZ).