A Severance Hospital research team has newly identified a cause of retinoblastoma.

Retinoblastoma is a white tumor that occurs in the retina and is the most common malignant tumor inside the eye of children. It can occur in one or both eyes. The most common symptom is a white pupil due to the tumor, leading to vision loss and potential strabismus.

As it progresses, it can cause eye pain and protrusion. It is usually diagnosed before the age of five, and about 40 percent of the cases are hereditary, which means that the cancer occurs from birth with abnormalities in the RB1 cancer suppressor gene in all cells.

During such cases, one RB1 mutation is present from birth, and retinoblastoma can occur if a natural mutation happens in the opposite RB1 allele.

In non-hereditary cases, both RB1 alleles must naturally malfunction for retinoblastoma to develop, typically leading to a later diagnosis.

Until now, other than the RB1 gene, the MYCN gene was the only known gene associated with the development of retinoblastoma.

To expand the options for diagnosing retinoblastoma, the team, led by Professors Lee Seung-kyu and Kim Yong-joon of the Department of Ophthalmology, and Han Jung-woo of the Department of Pediatric Hematology at Severance Hospital, conducted genetic tests for hereditary cancer panels to identify congenital genetic factors that increase the risk of cancer in the blood of 30 patients with retinoblastoma who visited Severance Hospital from March 2017 to Oct. 2021.

Out of the 30 patients with retinoblastoma, six patients were found to have mutations in the BRCA1/2 or BRCA-related BRIP1 gene in one allele of all cells.

In silico pathogenicity assessment using tools like ACMG variant classification and genomic sequence analysis revealed potential pathogenicity in five out of the six patients with BRCA1/2 or BRIP1 gene mutations.

For one patient, the microbiopsy of tumor fragments enabled genetic analysis of tumor cells.

This patient, classified as non-hereditary, did not have RB1 mutations in all cells as the genetic analysis of the tumor cells showed an RB1 mutation in only one allele, with no mutation or epigenetic changes in the opposite RB1.

However, a BRCA1 gene mutation was present in one allele of all cells, and epigenetic changes in tumor cells suggested a potential contribution to the development of retinoblastoma.

“This study confirms the pathogenic role of BRCA genes in the development of retinoblastoma,” Professor Lee said. “Further research may lead to the development of targeted therapies for retinoblastoma.”

The results of the research were published in the British Journal of Ophthalmology.