Two tiny genetic variations can predict which patients with Hodgkin's lymphoma are most likely to develop radiation-induced second cancers years after treatment, according to a genome-wide association study (GWAS) published online July 24 in Nature Medicine. Knowing in advance who is at risk could help physicians tailor treatment to reduce the risks for patients who are most susceptible to long-term damage.

Hodgkin's lymphoma is one of the most treatable cancers, with more than 90 percent of patients surviving after a combination of radiation and chemotherapy. But nearly 20 percent of patients treated as children develop a second cancer within 30 years. The younger the patients are when treated and the higher the radiation dose, the greater the risk. This late side effect of treatment is the second leading cause of death for long-term Hodgkin's survivors.

However, risk appears to vary by haplotype. If a patient has the protective haplotype, the study indicated a risk of second cancer at 3 percent, but for a patient with the risk haplotype, the risk is one in three, Kenan Onel, MD, PhD, associate professor of pediatrics at University of Chicago and senior author of the study, told Health Imaging News.

Onel and colleagues analyzed the genomes of 178 Hodgkin's patients who had been treated between the ages of 8 and 20 with chemotherapy and radiation therapy. Within 30 years after treatment, 96 of them had developed second cancers and 82 had not.

When they scanned each patient's genome, focusing on 665,313 genetic variations, they found three variations that appeared far more often in patients with second cancers. When they repeated the study using a different set of patients—62 cases with second cancers and 71 without—two of the three markers were significant.

The two markers are positioned near a gene known as PRDM1. The genetic variations are closely associated with increased cancer risk, and with each other, and appeared to decrease activation of the PRMD1 gene. Cells with the protective version of both markers expressed PRDM1 after being exposed to radiation. Cells with the variants linked to subsequent cancers did not produce PRDM1.

Previous studies have found that PRDM1 is involved in a variety of fundamental cellular processes, including proliferation, differentiation and apoptosis.

"This finding means we can better identify children who are most susceptible to radiation-induced cancers before treatment begins and modify their care to prevent this serious long-term complication," said Onel. "Luckily our options for Hodgkin's are broad enough that we can find ways to control the initial disease without relying on radiation therapy."

Despite the optimism regarding the findings, Onel hesitated to proclaim the results ready for prime time. “It’s based on a relatively small sample size. The data support [its application], but I don’t know if the impact is really that large.”

Onel and colleagues plan a two-pronged approach to future research. They are trying to connect with other groups to locate additional Hodgkin’s survivors to test the findings, and are searching for other radiation-exposed patients to determine if the variants play a role in apparently sporadic cancers.

"[The study] is also a triumph for GWAS," he added. "Many previous GWAS found multiple genetic differences, with each of them playing only a modest role, with minimal impact on clinical management. In this study, which focused on the interaction between genes and a very specific environmental factor—cancer long after radiation therapy—a small number of genetic differences produced a very big impact."

This study should also "bring some optimism" back to GWAS, Onel added. Most previous cancer-related markers found through GWAS have been "of little clinical value for predicting risk, response to therapy or survival." But by incorporating environmental exposure, such as radiation therapy, into genomic investigations, "much of the missing heritability can be revealed," he said. "By folding in the environmental component, we were able to ask a more targeted question. This approach could improve our ability to integrate genomics into routine cancer care."