RB or Not RB

CHLA is a world leader in the research and treatment of retinoblastoma, the No. 1 malignant eye tumor in children.

Retinoblastoma (or RB) 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.

A common sign of this cancer is a white glow or glint in the pupil of one or both eyes. Parents may first notice the condition when looking at their child in a photograph. The child’s pupil does not have the normal red appearance that a flash photo creates. Instead, the pupil is white.

Left untreated, retinoblastoma can be fatal or result in blindness. It also plays a special role in explaining cancer; retinoblastomas have been found to grow 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.

David E. Cobrinik, MD, PhD, of The Vision Center at Children’s Hospital Los Angeles, together with colleagues at Memorial Sloan-Kettering Cancer Center in New York City, has answered the longstanding question of why mutations to the RB1 gene primarily cause tumors of the retina and not other cell types. His study could reveal new cellular signaling pathways relevant to retinal development, cancer development and, ultimately, the discovery of novel therapies.

“Finding the single genetic change that causes these retinal tumors in young children advances our understanding of cancer, not only because it solves the RB riddle, but because the discovery more generally implies 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,” says Cobrinik, who is also an investigator with The Saban Research Institute of CHLA and associate professor of Ophthalmology at the USC Eye Institute in the Keck School of Medicine of the University of Southern California.

The RB1 gene encodes a tumor suppressor protein, referred to as Rb, which prevents excessive cell growth by regulating cell division. If both alleles of the RB1 gene are mutated early in life, the Rb protein is inactivated, resulting in development of retinoblastoma cancers.

The scientists found that retinoblastomas originate in a particular type of cell in the eye called cone photoreceptor precursors. Cone cells, or cones, are one of the two types of photoreceptor cells in the retina and are responsible for color vision. A cone precursor is an immature cone cell that is not yet fully differentiated.

“We found that loss of the RB1 gene results in abnormal proliferation because the cone precursor cells lack a self-monitoring ‘surveillance system,’ which would normally cause aberrantly proliferating cells to undergo cell death. Instead, cells are able to divide uncontrollably and eventually become cancerous,” Cobrinik explains.

Researchers at CHLA were also among the first to isolate and clone the RB1 gene. The Vision Center at CHLA, one of the largest clinical programs in the U.S. for the treatment of retinoblastoma, was among the first sites in the nation to offer gene testing for all retinoblastoma patients and the first to offer a prenatal diagnosis for the disease.

In June 2014, a team of CHLA physicians and scientists announced development of a retinoblastoma next-generation (RB1 NextGen) sequencing panel. The hospital became the first to offer this whole-gene sequencing to patients and family members who may also have inherited the gene mutation, placing them at high risk.

In germ-line cases—where a lineage of cells passes down genetic information from one generation to the next—the disease-causing mutation is inherited and is present in cells throughout the body. This can result in tumors in both eyes, as well as in other locations. Therefore, early detection and accurate diagnosis are critical to determining the best course of treatment.

“We used to think that if a child had a tumor in one eye and not in the other eye, it was a result of a somatic mutation, meaning that it wasn’t inherited. So we believed removal of the tumor stopped the cancer,” says Thomas Lee, MD, director of The Vision Center. “But now we know that 10 to 15 percent of those children who had an apparent somatic mutation are actually carrying a germ-line mutation, putting them at risk of developing subsequent tumors during adolescence or early adulthood.“

Lee adds that the ability to determine the existence of RB1 germ-line mutations early has significant implications—not only for the prognosis of a new patient with retinoblastoma, but for siblings who could also be at risk and, eventually, for a patient’s own children.

With a legacy of treating hundreds of children with retinoblastoma, CHLA now has the ability to also offer this unique and comprehensive screening test to survivors of the disease and their family members, as well as to patients at other cancer centers.

“We believe that siblings and children of carriers of the germ line should be tested immediately after birth,” says Lee, “because by detecting the gene mutations early, we can save a patient’s vision.”