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Epigenetic Shifts in Retinoblastoma Hint at Potential Treatment Target

NEW YORK (GenomeWeb News) – Researchers at St. Jude Children's Research Hospital and Washington University reported today that they have used genetic and epigenetic analyses to uncover the mechanism behind retinoblastoma formation — a discovery that may lead improved treatment strategies for the eye cancer.

Retinoblastoma is a rare tumor of the retina that develops during childhood and is known to involve mutations in a gene called RB1. Prior to the latest study, though, there was some debate over whether RB1 mutations spurred chromosome instability and mutations in retinoblastoma genomes or whether these variants influenced cancer risk in another way.

By doing whole-genome sequencing of matched primary tumor and normal samples from four children with retinoblastoma, combined with expression and epigenetic studies, members of the Pediatric Cancer Genome Project led by St. Jude and Wash U have found the answer to this ongoing puzzle.

Their findings, published online today in Nature, indicate that changes to RB1 lead to retinoblastoma development via epigenetic pathways, with most retinoblastoma genomes harboring only modest mutational burdens.

"These tumors contain very few mutations or chromosomal rearrangements," co-corresponding author Michael Dyer, a developmental neurobiology researcher at St. Jude's, said in a statement. "To our surprise and excitement, what we found was that instead of cancer genes having genetic mutations, they were being epigenetically regulated differently than normal cells."

Dyer and his colleagues used paired-end sequencing to sequence the genomes of primary retinoblastomas and matched normal tissues from four individuals with locally invasive tumors but no metastases. In the process, they generated almost 29x average genome coverage for the samples and around 24x average coverage of exons.

All told, the team found 668 verified somatic mutations in the genomes — an average of 167 per individual — and 40 structural variations. Just a handful of the mutations were predicted to change the amino acid composition of resulting proteins.

A screen of the 11 genes affected by these changes in dozens more retinoblastoma samples suggested that BCOR is the only gene besides RB1 with recurrent mutations in the tumors. It was mutated in 13 percent of retinoblastomas tested.

The genome of a primary tumor used to create a mouse xenograft model of the disease also remained relatively stable, even after being grown in vivo for nine months. The xenograft genome contained 67 single-base mutations and four structural variations not found in the primary tumor from which it was generated, researchers reported, but none of these produced changes to annotated genes.

In contrast, though, the team's chromatin immunoprecipitation, DNA methylation, and gene expression experiments — done using primary tumor and/or xenograft samples — suggested that the retinoblastoma genome is subject to dramatic epigenetic changes compared to the normal human fetal retina genome.

Researchers detected more than 100 genes showing altered epigenetic regulation in retinoblastoma, including 15 genes with known ties to cancer.

Those epigenetic shifts corresponded to gene expression changes as well, including a sharp rise in the expression of spleen tyrosine kinase SYK, a blood development-related gene that's believed to help some types of tumors survive and thrive. The SYK protein product was also highly expressed in additional retinoblastoma samples screened but not in normal retina tissue.

Consistent with their hypothesis that the jump in SYK expression spurs retinoblastoma growth, the team found that it could prompt apoptotic death in retinoblastoma cells or xenografts by targeting SYK with chemicals such as BAY 61-3606 or R406, drugs that have been tested for treating leukemia in preclinical trials.

The researchers are working on strategies for effectively delivering the R406 drug into the eye in a clinical setting and eventually hope to embark on a Phase I trial of the compound for treating retinoblastoma.