Genetic Retinoblastoma Risk Stratified by Age Among Patients with Metachronous Bilateral Conversion

Age at diagnosis may change genetic risk stratification for patients with metachronous bilateral conversion, with RBI variant-positive patients diagnosed ≥9 months according to a recent study.¹

Retinoblastoma, caused by biallelic inactivation of the retinoblastoma transcriptional corepressor 1 gene (RB1), affects roughly 1 in 16,000-18,000 live births. Currently, survival rates exceed 95% in high-income settings. However, surveillance optimization is still lacking, particularly among children with unilateral disease.²

“Advances in molecular diagnostics have improved risk counseling by detecting germline RB1 variants, low-level mosaicism, and non-RB1 mechanisms, such as MYCN amplification with minimal fellow-eye risk,” wrote Erkuan Dai, MD, PhD, department of ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and colleagues. “Nevertheless, whether age at diagnosis can supersede RB1 genetic subtype in predicting metachronous bilateral conversion—and thereby guide pragmatic deescalation for low-risk children without compromising safety—remains uncertain in real-world practice.”¹

Dai and colleagues conducted a single-center, retrospective cohort study at Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine in Shanghai. Investigators screened children with unilateral retinoblastoma diagnosed between July 2010 and October 2024; those with unilateral disease at presentation and a follow-up duration of ≥6 months were included. Exclusion criteria were an insufficient follow-up period, missing clinical data, or bilateral retinoblastoma identified within 1 month of initial diagnosis.¹

Blood RB1 testing was performed using multiplex ligation-dependent probe amplification coupled with next-generation sequencing to detect point variants and large deletions or duplications. RB1 variant-positive patients had their mosaic status classified based on variant allele frequency <0.4% in peripheral blood being considered mosaic – variants with variant allele frequency ≥0.4% were considered germline.¹

A total of 1310 patients were initially screened, of whom 1108 were included. Median age rate at diagnosis was 22 years (interquartile range [IQR], 12-31.4 months), and 53.3% of patients were male. Of the included patients, 62 (5.6%) were RB1 variant positive, 254 (22.9%) were RB1 variant negative by peripheral blood testing, and 792 (71.5%) were untested.¹

Over a median follow up of 43.4 months (IQR, 24.2-67.6), 2.2% of patients (n = 24) patients developed metachronous bilateral involvement. These conversion rates differed by genetic status – 24.2% (15/62) of RB1 variant-positive patients vs 1.6% (4/254) of RB1 variant-negative patients, with a difference of 22.6% (95% CI, 13.4-34.6; P <.001).¹

Cumulative incidence of metachronous bilateral conversion was then estimated, defining the primary end point as time from index diagnosis to first fellow-eye involvement. Most of these events occurred within 24 months, followed by a prolonged flat tail. The 24-month cumulative incidence was 2.2% (95% CI, 1.3-3.1), and stratification by genetic status showed early and sustained separation with a substantially higher risk among RB1 variant-positive patients. At 24 months, cumulative incidence had risen to 24.8% (95% CI, 13.8-35.9) in RB1 variant-positive patients and 1.6% (95% CI, 0-3.1) in RB1 variant-negative patients, with a difference of 23.2% (95% CI, 12.1-34.3; P <.001).¹

Among patients who were RB1 variant-positive patients, risk clustered among those diagnosed prior to 9 months, while no conversions were observed with those older than 9 months. A total of 4 RB1 variant-negative patients initially diagnosed at later ages converted – Dai and colleagues determined that these cases represented undetected low-level mosaicism, somatic variants below detection thresholds, or rare genomic events.¹

“Taken together, these data support surveillance that is triggered by genetic status and calibrated by age at diagnosis: intensify examinations for RB1 variant-positive infants diagnosed before 9 months during the first 24 months; deescalate thereafter if no conversion has occurred; and apply a lower-intensity schedule for RB1 variant-negative patients and RB1 variant-positive children diagnosed later, with explicit safeguards for the rare late conversions observed in genetically negative cases,” Dai and colleagues wrote.¹

References

1. Dai E, Xiao H, Zhao R, et al. Bilateral conversion risk in unilateral retinoblastoma using age and genetic testing. JAMA Ophthalmology. Published online March 12, 2026. doi:10.1001/jamaophthalmol.2026.0143

2. Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93(9):1129-1131. doi:10.1136/bjo.2008.150292