Risk of Second Tumors in Retinoblastoma Survivors after Ionizing Radiation: A Review

Abstract

Retinoblastoma (RB) is the most common ocular neoplasm in children, whose development depends on two mutational events that occur in both alleles of the retinoblastoma susceptibility gene (RB1). Regarding the nature of these mutational events, RB can be classified as hereditary if the first event is a germline mutation and the second one is a somatic mutation in retina cells or nonhereditary if both mutational events occur in somatic cells. Although the rate of survival of RB is significantly elevated, the incidence of second malignant neoplasms (SMNs) is a concern, since SMNs are the main cause of death in these patients. Effectively, RB patients present a higher risk of SMN incidence compared to other oncology patients. Furthermore, evidence confirms that hereditary RB survivors are at a higher risk for SMNs than nonhereditary RB survivors. Over the decades, some studies have been performed to better understand this subject, evaluating the risk of the development of SMNs in RB patients. Furthermore, this risk seems to increase with the use of ionizing radiation in some therapeutic approaches commonly used in the treatment of RB. This review aims to clarify the effect of ionizing radiation in RB patients and to understand the association between the risk of SMN incidence in patients that underwent radiation therapy, especially in hereditary RB individuals.

Keywords: RB1 gene; ionizing radiation; retinoblastoma; second malignant neoplasms.

Figure 1

Representation of the protein encoded by RB1, the retinoblastoma protein, pRB. This protein comprises 928 amino acids. The small pocket (A/B domain separated by a spacer region) binds with the LXCXE motif of viral oncoproteins. The large pocket interacts with E2Fs, suppressing their transcription, and binds with the oncoproteins, c-Ab1 and MDM2. Furthermore, this region contains a short peptide region that is competitively bound by CDKs or PP1. Created with BioRender.com.

Figure 2

Role of pRB in the regulation of the cell cycle. (a) During the G1 phase of the cell cycle, pRB is dephosphorylated by PP1. The dephosphorylated form of this protein can form a complex with E2Fs, blocking its activity and, consequently, repressing transcription. E2Fs are responsible for the activation of the transcription of genes that encode the proteins required for the progression to the S phase, such as DNA polymerase, dihydrofolate reductase, and human cyclin-dependent kinase 1 (CDK1). In the final stages of G1 and continuing to the M phase, CDKs mediate pRB phosphorylation, leading to the release of E2F and, consequently, to the expression of genes that play an important role in cell division. Later in the cell cycle, the dephosphorylation of pRB by PP1 re-establishes pRB in the unphosphorylated form. (b) pRB is a negative regulator of the cell cycle. In response to DNA damage, CDKs are inhibited by the activation of checkpoints. pRB remains in the dephosphorylated form and bonded to E2F. Under these conditions, the cell is prevented from transitioning to the G1 checkpoint. The presence of a pRB mutation promotes uncontrolled cell cycle progression and, consequently, tumorigenesis. Created with BioRender.com.