The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma

Abstract

Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the RB1 gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families.

Keywords: cell-free DNA; liquid biopsy; noninvasive prenatal diagnosis; retinoblastoma.

Figure 1

Noninvasive prenatal diagnosis (NIPD). The blood of a pregnant woman contains both maternal and foetal-derived cell-free DNA. Genetic analysis of the cell-free foetal DNA by NIPD can determine whether a fetus has inherited a pathogenic variant. Variants can be detected directly, or an indirect analysis, such as the relative haplotype dosage (RHDO) analysis, can be used.

Figure 2

Sampling cell-free DNA in aqueous humour from a retinoblastoma eye. Tumour-derived cell-free DNA is present in the vitreous and aqueous humour. Approximately 100 µL of aqueous humour is collected using a 32-guage needle.