Genome maintenance in retinoblastoma: Implications for therapeutic vulnerabilities

Retinoblastoma (RB) is a pediatric ocular malignancy that is initiated mostly by biallelic inactivation of the RB transcriptional corepressor 1 (RB1) tumor suppressor gene in the developing retina. Unlike the prevailing prediction based on multiple studies involving RB1 gene disruption in experimental models, human RB tumors have been demonstrated to possess a relatively stable genome, characterized by a low mutation rate and a few recurrent chromosomal alterations related to somatic copy number changes. This suggests that RB may harbor heightened genome maintenance mechanisms to counteract or compensate for the risk of massive genome instability, which can potentially be driven by the early RB1 loss as a tumor-initiating event. Although the genome maintenance mechanisms might have been evolved to promote RB cell survival by preventing lethal genomic defects, emerging evidence suggests that the dependency of RB cells on these mechanisms also exposes their unique vulnerability to chemotherapy, particularly when the genome maintenance machineries are tumor cell-specific. This review summarizes the genome maintenance mechanisms identified in RB, including findings on the roles of chromatin regulators in DNA damage response/repair and protein factors involved in maintaining chromosome stability and promoting survival in RB. In addition, advantages and challenges for exploiting these therapeutic vulnerabilities in RB are discussed.