Major finding: SYK is upregulated by nongenetic mechanisms in retinoblastoma.
Concept: Epigenetic deregulation of cancer pathways may be important in genomically stable tumors.
Impact: Small-molecule SYK inhibitors may be considered for retinoblastoma therapy.
The underlying mechanism of retinoblastoma formation following RB1 biallelic inactivation remains poorly understood. Zhang and colleagues sought to identify cooperating genetic alterations that drive retinoblastoma progression by performing whole-genome sequencing on 4 primary human retinoblastoma samples and matched normal tissue. Strikingly, the retinoblastomas had hardly any structural variations and an extremely low mutation rate. The exons of the few genes affected by missense mutations were sequenced in an additional 42 retinoblastomas, and only BCOR was found to be recurrently mutated in 6 samples. These findings were surprising given previous in vitro studies implicating the retinoblastoma protein (RB) in maintenance of genomic stability, and instead suggested that retinoblastomas were genomically stable and required few genetic lesions to develop other than biallelic RB1 loss. To determine the extent to which epigenetic changes contribute to retinoblastoma progression in the absence of genomic instability, the authors compared histone modifications, DNA methylation, and gene expression in primary retinoblastomas and normal retinas. Interestingly, the spleen tyrosine kinase (SYK), which has no known function in the developing eye and is not expressed in retinal cells, was strongly upregulated and marked by activating histone modifications. Immunohistochemical analysis of a larger cohort of retinoblastomas showed extremely strong SYK staining in all of 82 tumor samples. Retinoblastoma cells were specifically sensitive to SYK inhibition in vitro, and conjunctival administration of the small-molecule SYK inhibitor BAY 61-3606 improved outcome in an orthotopic retinoblastoma xenograft model. Together, these integrative analyses suggest that epigenetic changes are important in retinoblastoma etiology and identify SYK as a promising therapeutic target.
Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 2012;481:329–34.
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