Retinoblastoma beyond RB1: recent advances in genetic biomarkers

Retinoblastoma is an eye cancer that accounts for approximately 4% of all pediatric malignancies and is the most common malignant ocular tumor in children [1]. The disease can be unilateral (when it affects only one eye, as seen in two-thirds of patients) or bilateral (when it affects both eyes). Although most cases of retinoblastoma do not show family history, the importance of hereditary factors for this cancer is well established [2]. The familial disease is transmitted as a typical Mendelian autosomal dominant trait, with high penetrance. The heritable form affects all patients with bilateral retino blastoma and approximately 15% of patients with the unilateral form, is generally multi focal and is associated with increased risk of second primary cancers. Approximately 40% of retinoblastoma cases are heritable, meaning that patients are at risk of transmitting the disease to their offspring, although most heritable cases arise as sporadic disease. Nonheritable retinoblastoma, which occurs in approximately 60% of cases, is always unilateral, unifocal and is not associated with increased risk of other cancers. Clinical studies on retinoblastoma led to the identification of the first tumorsuppressor gene – retinoblastoma (RB1), located at 13q14 – and the development of the ‘two-hit’ model [3]. According to Knudson, in fact, two mutational events (M1 and M2) or ‘hits’ are required for tumor onset. Thus, an individual with a germline mutation – M1 – in a tumorsuppressor gene (inherited or occurring de novo) is predisposed to cancer because only another somatic mutation in the same gene – M2 – will be enough to knock out gene function and trigger tumor development [3].