Genomic landscape of retinoblastoma: Insights into risk stratification and precision pediatric neuro-oncology

Abstract Background Retinoblastoma is the most common intraocular malignancy of childhood, yet its genomic landscape remains incompletely defined, particularly in understudied populations. Beyond RB1 loss, the contribution of additional somatic and germline alterations to disease heterogeneity and clinical behavior is unclear. Methods We performed whole-exome sequencing of 166 retinoblastoma samples from 166 patients with matched germline DNA, representing the largest cohort analyzed to date. Clinical data were available for 160 patients. Variant calling, copy number alteration (CNA) profiling, and integrative analyses were performed to characterize genetic drivers and their associations with clinical features. Results Pathogenic RB1 variants were identified in 120 patients, and MYCN amplification in 6 patients. Additional recurrent alterations involved BCOR, CCND3, ERBB2, and PDGFRB. Copy number gains of 6p (41.3%) and 17q (8.1%) were significantly associated with high-risk features including rubeosis, subretinal seeding, and tumor extension beyond the lamina cribrosa. Germline ERBB2 variants correlated with orbital invasion, while germline PDGFRB variants were associated with second primary cancers. Together, these findings underscore the genetic heterogeneity of retinoblastoma and reveal novel genotype–phenotype correlations. Conclusions This study provides the most comprehensive genomic characterization of retinoblastoma to date, expands the known mutational spectrum, and identifies biomarkers with direct clinical relevance. These insights have the potential to refine risk stratification, inform precision therapeutic strategies, and improve long-term outcomes for children with retinoblastoma.