Genome Region Tied to Risk of Second Cancers after Radiation Therapy
A new study may provide an important clue about the long-term risk of second primary cancers in children with Hodgkin lymphoma who receive radiation therapy as part of their treatment. In the study, researchers identified two genetic variants, called single nucleotide polymorphisms (SNPs), in a region of chromosome 6 that were strongly associated with an increased risk of a second cancer in this group of cancer survivors.
Published July 24 in Nature Medicine, the study is among the first genome-wide association studies focused on second cancer risk, and one of the few such studies to date that limited the study population to a group that received a specific therapeutic intervention.
Approximately 90 percent of children and adolescents diagnosed with Hodgkin lymphoma are cured. But that cure can come at a price: Nearly 20 percent of survivors will develop a second cancer, which is the second leading cause of death in this population.
Researchers have struggled to identify which patients have an increased risk for a second cancer and should receive different treatments or should undergo more intensive surveillance for a second cancer as they grow older, explained the study's senior investigator, Dr. Kenan Onel of the University of Chicago.
That is part of what makes these findings so "tantalizing," Dr. Onel said. "In the setting of this exposure, [these variants] seem to have a large effect." Survivors with the risk-conferring SNPs were more likely to develop a second cancer than survivors without those SNPs.
But this was a relatively small study, he stressed, so larger studies will be required to confirm the findings. "Much more work is needed before we can say that this is something that doctors or patients can base treatment decisions on."
To find the chromosome region involved, Dr. Onel and his colleagues scanned the DNA of 178 survivors of childhood Hodgkin lymphoma treated with radiation, 96 of whom had developed second cancers. Three genetic variations (or SNPs) were associated with a higher risk of a second cancer.
—Dr. Lindsay Morton
Exactly how these genetic variants might increase cancer risk is unclear. But the region of chromosome 6 on which the variants reside is near a gene called PRDM1. Other studies (here and here) have recently identified PRDM1 as a possible tumor suppressor gene in a subtype of diffuse large B-cell lymphoma.
In additional experiments in cell lines, Dr. Onel and his colleagues showed that the presence of the risk variants, or alleles, was associated with lower levels of PRDM1 protein and that PRDM1 protein levels rose in response to radiation only in cells that had alleles "protective" against second cancers.
The researchers did not rule out the possibility that other genes may be involved, however.
To help clarify the roles of the two risk alleles when combined with radiation therapy in predisposing patients to second cancers, a similar analysis needs to be done that includes survivors who were not exposed to radiation, explained Dr. Lindsay Morton of the Radiation Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics (DCEG).
This study paves the way "for further investigations of the complex interplay between genetic susceptibility and environmental exposures involved in the development of second cancers," wrote Drs. Morton and Stephen Chanock, chief of DCEG's Laboratory of Translational Genomics, in an accompanying commentary. Future investigations need to assess the role of radiation dose and other treatments, such as certain types of chemotherapy, they wrote.
Another important future project, Dr. Onel said, will be to see if the findings apply to survivors of other childhood cancers.
There are nearly 12 million cancer survivors in the United States, and this number will continue to grow as treatments and diagnostic tools improve. "This study is an important first step toward identifying patients who may be at increased risk for a second cancer later in life," said Dr. Morton. "It is our hope that in the future we may be able to tailor health care for survivors more effectively to reduce the burden of second cancers."