Digital PCR Quantification of a Circulating RBP3 and CRX RNA Signature Establishes a Liquid Biopsy Framework for Precision Monitoring of Retinoblastoma.
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Retinoblastoma (RB) is the most common intraocular malignancy of childhood, yet molecular assessment of disease dissemination and minimal residual disease (MRD) remains challenging due to the contraindication of intraocular biopsy. Here, we evaluate the feasibility of cell-free RNA (cfRNA)- and circulating tumor cell RNA (ctcRNA)-based liquid biopsy for the sensitive detection of disseminated retinoblastoma using digital PCR (dPCR) targeting the retina-specific markers CRX and RBP3. We analyzed 433 bone marrow (BM), peripheral blood (PB) and cerebrospinal fluid (CSF) samples collected longitudinally from 50 patients with RB. dPCR assays demonstrated high analytical sensitivity. cfRNA detection showed complete sensitivity and negative predictive value in bone marrow compared with myelogram analysis, frequently identifying molecular positivity in cytologically negative samples. In cerebrospinal fluid, cfRNA detection was highly specific but less sensitive, reflecting compartment-specific biological constraints. Longitudinal analysis revealed that changes in CRX and RBP3 ctcRNA levels closely tracked treatment response, preceded cytological evidence of bone marrow involvement in several cases, and identified molecular persistence or re-emergence during follow-up, including after hematopoietic stem cell transplantation. Together, these findings demonstrate that cfRNA- and ctcRNA-based liquid biopsy using CRX and RBP3 enables sensitive and dynamic detection of disseminated retinoblastoma, particularly in bone marrow, and supports its potential utility for MRD monitoring. Longitudinal patient analyses will be required to define prognostic thresholds and establish the clinical role of this approach in risk stratification and long-term surveillance.