Researchers have answered the long-standing question of why mutations to a particular gene primarily cause tumors of the retina and not of other cell types.

Led by David Cobrinik, associate professor of ophthalmology at the USC Eye Institute, the study could reveal new cellular signaling pathways relevant to retinal development, cancer development and the development of novel therapies.

Conducted with researchers at Children’s Hospital Los Angeles and the Memorial Sloan-Kettering Cancer Center, the study is published in this week’s online issue of Nature.

Retinoblastoma is a childhood retinal tumor usually affecting children 1 to 2 years of age. Although rare, it is the most common malignant tumor of the eye in children.

“These findings significantly advance our understanding of cancer, not only because they solve the retinoblastoma riddle, but also because they more generally imply that cancers can develop through the collaboration between a cancer-causing mutation — in this case, inactivation of the RB1 gene — and cell type-specific circuitry,” said Cobrinik, an investigator with The Saban Research Institute of CHLA.

Retinoblastoma is a childhood retinal tumor usually affecting children 1 to 2 years of age. Although rare, it is the most common malignant tumor of the eye in children. Left untreated, retinoblastoma can be fatal or result in blindness. It has also played a special role in understanding cancer because retinoblastomas have been found to develop in response to the mutation of a single gene — the RB1 gene  — demonstrating that some cells are only a step away from developing into a life-threatening malignancy.

The RB1 gene encodes a tumor suppressor protein, referred to as Rb, which prevents excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. If both alleles of the RB1 gene are mutated early in life, the Rb protein is inactivated, resulting in development of retinoblastoma cancers. (While the Rb protein regulates proliferation in many cell types, only cells in the retina routinely form cancers when the function of the RB1 gene is lost.)

Additional contributors included first author Xiaoliang Xu, Lu Wang, David Abramson and Suresh Jhanwar, of Memorial Sloan-Kettering Cancer Center; Hardeep Singh and Dong-Lai Qi, The Saban Research Institute; and Bradford Poulos of the Albert Einstein College of Medicine. Funding for the study was provided in part by the National Institutes of Health (grant number 1R01CA137124).

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