But that mutation, Howard Hughes Medical Institute (HHMI) researchers have now discovered, changes the way cells turn on and off many other genes. The finding explains why retinoblastoma occurs at such a young age and suggests a new avenue for treating the cancer.
Most cancers are caused by a process that spans decades. Cells gradually accumulate mistakes as they are copied again and again. When enough mistakes—in the form of genetic mutations—have built up, the cells don’t function normally anymore and start to resemble cancer, growing out of control. This is why the risk of most cancers increases with age. But retinoblastoma appears in newborn babies—it’s even been seen in infants born prematurely.
“It’s been considered a big paradox. How can retinoblastoma progress so quickly and acquire all the hallmarks of cancer? ”
Michael A. Dyer
“It’s been considered a big paradox,” says Michael Dyer, an HHMI early career scientist at St. Jude Children’s Research Hospital. “How can retinoblastoma progress so quickly and acquire all the hallmarks of cancer?” In a study published January 11, 2012 in the journal Nature, Dyer and colleagues provide an answer to that question.
Cancers are characterized by defects in multiple pathways. Cancer cells live longer than other cells, don’t die when exposed to factors that normally kill cells, divide and grow more quickly, and reorganize blood vessels and other tissues surrounding them. A single gene can’t make all these changes.
But scientists knew that a mutation in a single gene, RB1, was enough to cause retinoblastoma. “Historically, the theory on retinoblastoma has been that this mutation in RB1 causes massive genome instability,” says Dyer. “Chromosomes start to acquire breaks and the genome gets all scrambled.” The scrambling of genes, researchers thought, explained how so many pathways stopped functioning correctly.
But when Dyer and his colleagues took tumors that had been surgically removed from childrens’ eyes and implanted them into the eyes of mice, they saw little evidence of genome instability.
“The tumors started growing and invading tissue almost immediately,” says Dyer, “behaving in the mice just as they had behaved in the human patients.” But when they tracked the genes in the tumors over time, nothing changed. All the genes remained the same for as long as nine months after the tumors were implanted in the mice.
“If RB1 mutations are causing genetic instability, then the more a tumor grows, the more scrambled the genes should become,” says Dyer. He saw no evidence of this. So he began to wonder how RB1 was causing so much cellular misregulation. He started to think that the answer might be explained by epigenetics, factors that influence the way genes are turned on and off, without altering DNA sequence.
Dyer’s team collected samples of retinoblastoma tumors and of normal eye tissue and compared them. They looked at chemical modifications that can turn genes on and off – known as epigenetic changes, as well as large structural changes that can determine which genes produce proteins. They also measured the amount of different genes that the cells were producing. In particular, they focused on genes known to have cancer-causing mutations.
“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,” says Dyer.
One gene jumped to the researchers’ attention. Called SYK, it’s known to cause leukemia when it’s mutated. It’s not turned on in normal eye tissue, but in the retinoblastoma samples, it was turned on to high levels.
There’s already a drug that blocks SYK being tested for both leukemia and rheumatoid arthritis, so Dyer had an easy way to turn the gene’s levels down. And when he blocked SYK with the drug, the tumor cells died—both in cancer cells grown in the lab as well as tumors in the eyes of mice.
Moreover, when Dyer looked at 82 retinoblastoma samples from humans, all 82 had high levels of the protein made by SYK. None of the normal eye samples did.
Even though there’s no mutation in SYK in retinoblastoma, Dyer says, RB1 influences the way cells turn genes on and off. Their experiments show that Rb turns on SYK, while it turns down the expression levels of other genes. The researchers have yet to work through the rest of the list of epigenetic differences they uncovered in retinoblastoma.
There’s likely many epigenetic changes influencing other cancer types, says Dyer, but it’s harder to sort out since there can also be thousands of gene mutations. In the case of retinoblastoma, scientists now know that it’s one gene mutation causing a plethora of epigenetic changes. Whether they can block those changes, or target them with drugs one by one, it’s a leap in understanding a devastating cancer.
Howard Hughes Medical Institute.