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New Test Detects Parent-of-Origin in Retinoblastoma

Origin matters for this hereditary ocular cancer because researchers found that male and female copies of the mutation are associated with different disease trajectories, and so would likely influence physicians' treatment recommendations.

Ophthalmology Management February 3, 2025

Two ophthalmologists at Seattle Childen’s Hospital who specialize in pediatric retinoblastoma care have developed a novel blood test that can tell which parent’s DNA carried the RB1 gene mutation.

That distinction is meaningful, according to a press release from the University of Washington (UW) School of Medicine, because the researchers found that male and female copies of the mutation are associated with different disease trajectories, and so likely would influence doctors’ treatment recommendations.  

“Depending on which copy you have, that could reflect the cancer’s severity and its likely response to chemotherapy,” said Debarshi Mustafi, MD, PhD, one of the researchers and an assistant professor of ophthalmology at the University of Washington School of Medicine. “When mutations came from the maternal copy, patients’ eyes were saved more often,” Dr. Mustafi said. “If they got it from the paternal DNA, we are less likely able to save the eye. Our preliminary data also shows that a secondary cancer such as sarcoma is more likely with the paternal mutation.”  

In a patient whose retinoblastoma stems from maternal inheritance, left, there is only a small tumor in the eye (denoted by white arrow) that responded well to treatment. Comparatively, in a patient with paternal inheritance, an extensive tumor burden affects underlying retinal structures. Image courtesy of Dr. Debarshi Mustafi
In a patient whose retinoblastoma stems from maternal inheritance, left, there is only a small tumor in the eye (denoted by white arrow) that responded well to treatment. Comparatively, in a patient with paternal inheritance, an extensive tumor burden affects underlying retinal structures. Image courtesy of Dr. Debarshi Mustafi

The new gene-sequencing technique that powers the blood test can also detect parent-of-origin even when the child carries a de novo variant, one that arises spontaneously and is not present in either parent. These de novo cases, according to the press release, are the predominant cause of all cancers and account for 90% of all inherited cases of retinoblastoma. Dr. Mustafi believes the new test likely will have applications for other genetic diseases in which parent-of-origin influences patients’ risk.

The findings were published Dec. 26, 2024 in the journal JCI Insight. Andrew W. Stacey, MD,  an associate professor of ophthalmology at the UW School of Medicine, is coauthor.