MYCN Is Amplified in Retinoblastomas without RB1 Mutation

Biallelic loss of RB1 is thought to underlie all cases of retinoblastoma, a childhood cancer of the developing retina. However, Rushlow and colleagues found in the course of clinical work that approximately 3% of unilateral retinoblastomas do not have any evidence of RB1 mutations, promoter hypermethylation, or loss of heterozygosity. Strikingly, MYCN copy number was elevated in 90% of these RB1⁺/⁺ retinoblastomas, compared with 65% of RB1-deficient retinoblastomas, and 53% of the RB1⁺/⁺ tumors had acquired 28 or more copies of MYCN, whereas high-level MYCN amplification was not observed in any RB1⁻/⁻ tumor. MYCN-amplified, RB1⁺/⁺ retinoblastomas expressed full-length, nuclear, functional RB1 protein that was normally hypophosphorylated and hyperphosphorylated and capable of binding E2F1. These tumors expressed embryonic retinal markers and arose in the retina, suggesting they were retinoblastomas, but they were molecularly, histologically, and clinically distinct from RB1⁻/⁻ retinoblastomas. Copy number abnormalities characteristic of RB1⁻/⁻ retinoblastomas were significantly less common in MYCN-amplified, RB1⁺/⁺ retinoblastomas, and MYCN-amplified, RB1⁺/⁺ tumors were generally more genomically stable than RB1⁻/⁻ tumors, providing support for a driving role of MYCN amplification in the initiation of these retinoblastomas. Histologic hallmarks of RB1⁻/⁻ retinoblastomas were absent in MYCN-amplified, RB1⁺/⁺ retinoblastomas, which instead had cellular features similar to those of other MYCN-amplified tumors. Clinically, MYCN-amplified, RB1⁺/⁺ retinoblastomas were larger and more invasive than RB1⁻/⁻ retinoblastomas and were diagnosed at a significantly younger median age (4.5 months vs. 24 months). These findings show that not all retinoblastomas are caused by RB1 loss and identify a retinoblastoma patient population that may especially benefit from aggressive treatment, such as eye removal, and potentially respond to therapies that exploit MYCN dependency.

Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S, Thériault BL, et al. Characterisation of retinoblastomas with RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 2013;14:327–34.

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