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Researchers Detect Variants Tied to Second Cancer after Hodgkin's Treatment in Childhood

By Andrea Anderson

NEW YORK (GenomeWeb News) – Two genetic variants are associated with increased risk of second cancers called "radiation therapy-induced second malignant neoplasms" (SMNs) in individuals treated for Hodgkin's lymphoma in childhood, researchers reported in Nature Medicine online yesterday.

The American and Canadian group did a genome-wide association study involving nearly 200 individuals treated for Hodgkin's disease with radiation as children. When they compared genetic patterns in the Hodgkin's survivors who did and did not develop radiation-related second cancers within about 30 years of receiving this therapy, the researchers found two SNPs that were significantly associated with these SMN cancers. Both variants fell near the chromosome 6 gene PRDM1, which codes for a transcriptional repressor.

Based on findings from their GWAS and follow-up experiments, those involved in the study speculate that PRDM1 may be a key player in a genetic system response to radiation exposure, perhaps acting as a tumor suppressor in this context.

"The idea is that different exposures are going to activate different cellular responses and each of those different cellular responses is going to have its own set of genetic determinants," senior author Kenan Onel, a pediatrics and cancer biology researcher at the University of Chicago, told GenomeWeb Daily News.

"It's so important to think about our genetic associations in the context of the exposures that drive them," he added.

Although Hodgkin's lymphoma treatment is usually quite effective, some 18 percent of those who beat the disease as children go on to develop SMNs within 30 years, Onel and his co-authors noted. These second cancers seem to be related to the radiation used to target the original cancer, and typically occur in skin and other tissues that were exposed to this radiation during Hodgkin's treatment.

"Despite the clinical importance of this devastating late consequence of radiation therapy exposure, little is known about predisposing risk factors," Onel and his co-authors wrote. "We performed a [GWAS] to identify variants associated with radiation therapy-induced SMNs in Hodgkin's lymphoma survivors."

The team used the Affymetrix SNP 6.0 array to genotype 178 individuals who had been treated for Hodgkin's disease between the ages of eight and 20 years old, including 96 individuals who had developed an SMN cancer within six to 34 years of treatment and 82 who had not developed a second cancer over 27 to 38 years of follow up.

In the process, the researchers found three suspicious SNPs — two on chromosome 6 and one on chromosome 18 — that they went on to test in another 62 Hodgkin's survivors who'd developed a second cancer and 71 who hadn't. The two chromosome 6 variants, both between the ATG5 and PRDM1 genes, were significantly associated with SMN development in this replication group.

Researchers did not find significant associations between these SNPs and SMNs in yet another group of individuals treated for Hodgkin's lymphoma as adults, though Onel noted that these individuals tend to be less prone to second cancer in general than those treated when they're younger.

"There is an inverse association with age," he said. "So if you're treated [for Hodgkin's lymphoma] under the age of 20, you're at high risk for second cancers and if you're treated over the age of 20 you're at a much lower risk."

Still, he added, because the number of adults tested was relatively small, it's possible that the SNPs have an effect that was simply too subtle to detect in this group.

The team's subsequent experiments indicate that the newly identified risk alleles coincide with lower expression of the PRDM1 gene. And while their cell line experiments suggest that PRDM1 levels are usually ramped up in cells exposed to radiation, they found that the gene's expression is muted in radiation-exposed lines carrying the less favorable SNPs.

"Taken together, our findings support a previously unknown role for PRDM1 as a radiation-responsive tumor suppressor," the study authors wrote. "However, we cannot rule out either long-range effects of these variants on other genes or tissue-specific differences in PRDM1 function."

PRDM1, also known as BLIMP1, has been implicated in the development of B-cells and other cell types, Onel noted. And because SNPs in the same region as those identified in the current study have previously been linked to both autoimmune disease and non-Hodgkin's lymphoma, he explained, the team is interested in exploring whether immune function and/or inflammation might contribute to second cancers in Hodgkin's survivors.

The researchers are also doing follow-up studies to look at PRDM1 function in more detail, including research aimed at finding factors that signal to PRDM1 when cells are exposed to radiation and downstream targets of PRDM1 that could contribute to radiation response.

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