Mentor Name: Jesse Berry

Our research aligns with the mission of Alex’s Lemonade Stand Foundation by addressing critical gaps in the molecular characterization of retinoblastoma. Retinoblastoma is the most common pediatric eye cancer, typically diagnosed in infants and young children under the age of three. A major challenge in managing this disease is that tumor biopsy cannot be performed due to the risk of extraocular tumor spread. As a result, diagnosis and risk assessment rely primarily on clinical examination, limiting access to tumor-derived molecular information that could otherwise inform genetic counseling, prognosis, and long-term care. Consequently, our understanding of the genomic features underlying retinoblastoma remains constrained. Pioneering work from the Berry/Xu Laboratory demonstrated that aqueous humor (AH), a clear fluid safely collected from the eye during routine procedures, contains tumor-derived cell-free DNA and can serve as a proximal liquid biopsy for retinoblastoma. Analysis of AH-derived DNA enables access to tumor genomic information without invasive tissue sampling and has expanded opportunities for molecular characterization in this disease.

The proposed project leverages a clinically implemented, clinical-grade targeted sequencing assay (LBSeq4Kids) applied to AH-derived DNA to characterize RB1 first and second hits in retinoblastoma patients. The study will survey RB1 mutation detection and characterize the spectrum of pathogenic alterations observed in AH samples, including single-nucleotide variants, insertions and deletions, and copy number alterations. By examining these genomic features across a clinical cohort, this work aims to define how aqueous humor liquid biopsy captures RB1 two-hit inactivation and variant diversity. Overall, this project provides a foundational framework for understanding RB1 genomic alterations detectable through aqueous humor liquid biopsy and supports ongoing efforts to integrate clinically derived genomic data into the molecular characterization and clinical management of retinoblastoma.