Faulty genes, not just treatment side effects, to blame for double whammy
WASHINGTON — A second cancer later in life is common for childhood cancer survivors, and scientists now have a sense of the role genes play when this happens. A project that mined the genetic data of a group of survivors finds that 11.5 percent carry mutations that increase the risk of a subsequent cancer.
“We’ve always known that among survivors, a certain population will experience adverse outcomes directly related to therapy,” says epidemiologist and team member Leslie Robison of St. Jude Children’s Research Hospital in Memphis. The project sought “to find out what contribution genetics may play.” The team presented their work at the American Association of Cancer Research meeting April 3.
“This is a nice first step,” says David Malkin, a pediatric oncologist at the University of Toronto. “The results validate the thoughts of those of us who believe there is a genetic risk that increases the risk of second malignancies.”
Five-year survival rates for kids with cancer have grown to more than 80 percent. But “there are long-term consequences for having been diagnosed and treated for cancer as a child,” notes Robison. Some survivors develop a later, second cancer due to the radiation or chemotherapy that treated the first cancer (SN: 3/10/07, p. 157).
The researchers examined 3,007 survivors of pediatric cancer who routinely undergo medical evaluation at St. Jude. About a third had leukemia as children. By age 45, 29 percent of this group had developed new tumors, often in the skin, breast or thyroid.
The team cataloged each survivor’s DNA, and looked closely at 156 genes known as cancer predisposition genes. Of the survivors, 11.5 percent carried a problematic mutation in one of the 156 genes. Some genes on the list convey a higher risk than others, so the team looked further at a subset of 60 genes in which only one mutated copy in each cell is enough to cause disease. These 60 genes also have high penetrance, meaning that a mutated copy is highly likely to lead to a cancer. Nearly 6 percent of the survivors had a problematic mutation in one of these 60 genes.
The research team also separated the survivors based on whether or not they had received radiation therapy as children. Close to 17 percent of survivors not exposed to radiation therapy had a problematic mutation in the subset of 60 genes. These survivors had an increased risk for any second cancer. Those with both a mutation in one of the 60 genes and radiation in their treatment history had a higher risk for specific kinds of second cancers: breast, thyroid or sarcomas, tumors in connective tissues.
Based on the new estimates of genetic risk, the team suggests that survivors not given radiation therapy undergo genetic counseling if a second cancer develops. Counseling is also recommended “for survivors who develop a secondary breast cancer, thyroid cancer or sarcoma in a site that received prior radiation therapy,” says St. Jude epidemiologist and project team member Carmen Wilson. Counseling can provide guidance on health practices going forward, reproductive choices and the implications for immediate family members who may have inherited the mutation, notes Robison.
The extensive amount of medical and genomic information collected for the survivors could help with cancer prevention efforts in the future, Robison says. The team would like to create prediction models that consider treatment, genetics and other clinical information, in order to place survivors into different risk groups. “It’s eventually going to have clear implications for how these patients are clinically managed, and how we either prevent or ameliorate the adverse effects,” Robison says.
Malkin notes that not only “what you got for treatment, but when you got it” is another factor influencing a survivor’s risk profile for second cancers, as treatments and doses have changed over time. He also thinks the percentage of survivors at risk reported by Robison’s team is lower than expected. “Expanding the pool of genes to look at will be very informative,” he says.