The research brings us closer to optimizing treatment for children with retinoblastoma

The research brings us closer to optimizing treatment for children with retinoblastoma

Retinoblastoma is an eye cancer that occurs in infants and young children and can cause vision loss, loss of one or both eyes, and even death. Unlike most tumors, these cannot be biopsied because of the risk of the cancer spreading to the rest of the body. In 2017, Jesse Berry, MD, a surgeon and ocular oncologist at Children's Hospital Los Angeles, discovered that fluid removed from the eye during treatment for retinoblastoma contained tumor DNA and acted as a liquid biopsy - providing information about the tumor and opening the door to earlier diagnosis and treatment. In their lab's latest research, published in Nature Communications, the team found that aqueous humor could be used for prognosis in addition to diagnosis - ultimately making treatment decisions that lead to better outcomes for children with more aggressive disease.

Because retinoblastoma occurs in the back of the eye, it is not easy to detect. The condition is typically discovered when parents notice a glow in their young child's eye in low light conditions or after taking flash photos. In the past, the child was thought to have retinoblastoma, a genetic disease, and was treated without a definitive diagnosis. The treatment paradigm changed five years ago when Dr. Berry's research reported that tumor genetic material could be found in the fluid taken from the front of the eye - called aqueous humor. A confirmed genetic diagnosis became possible before any surgical procedure, allowing for earlier and more accurate diagnosis and treatment.

According to Dr. Berry, head of the ocular oncology and retinoblastoma program at CHLA, says her lab's latest discovery—the ability to use aqueous humor for prognosis—is equally significant.

As a clinician treating these patients, I was so frustrated because I saw two children who clinically looked the same and received the same treatment. A child would respond wonderfully. But the other child had a more aggressive tumor that did not respond to treatment or recurred. I felt like there had to be something happening at a cellular level that was responsible for what we were seeing. We now know that molecular analysis of aqueous humor can explain these differences.”

Dr. Jesse Berry, MD, surgeon and ophthalmic oncologist, Children's Hospital Los Angeles

Most retinoblastoma tumors arise from a mutation in the Rb gene. But the cancer can also arise from epigenetic changes - genes that are switched on to promote tumor growth and disease progression. One of the most significant epigenetic changes - called methylation - is caused by a chemical change in the gene that can turn a normal cell into a tumor cell. Methylation can “turn off” good, cancer-regulating genes and “turn on” unwanted, cancer-promoting genes. DNA methylation is a common tumor marker used for diagnosis and prognosis in many other malignancies.

The researchers aimed to determine the methylation status in aqueous humor samples associated with retinoblastoma. They identified a specific methylation signature indicative of aggressive tumors and 294 genes that were regulated by methylation to promote tumor growth.

“Reliable biomarkers are needed to guide treatment decisions for children with retinoblastoma,” says Liya Xu, PhD, principal investigator at CHLA and assistant professor at the Keck School of Medicine of USC. "By identifying additional genes that play a role in this cancer and seeing how these genes behave, we are paving the way for a whole range of potential therapeutic targets. This brings us ever closer to optimizing treatments to prevent blindness in these young people." Patients.”

Additional authors of the study include: Liya Xu (first co-author), Chen-Ching Peng, Kevin Schwanzek and David Cobrinik from the Vision Center at Children's Hospital Los Angeles and the USC Roski Eye Institute; Hong-Tao Li (first co-author), Daniel J. Weisenberger, Meng Li, Gangning Liang from USC Norris Comprehensive Cancer Center; and Wanding Zhou of Children’s Hospital of Philadelphia.

Source:

Children's Hospital Los Angeles

Reference:

Li, H.T., et al. (2022) Characterization of DNA methylation signatures of retinoblastoma using liquid biopsy of aqueous humor. Nature communication. doi.org/10.1038/s41467-022-33248-2.