July 25, 2011
New Discovery for Hodgkin’s Lymphoma
(Ivanhoe Newswire) "“ 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. New research has found two tiny genetic variations that can predict which patients with Hodgkin's lymphoma are most likely to develop radiation-induced second cancers years after treatment. 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.
Nearly 20 percent of patients treated for Hodgkin's lymphoma 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.
The study 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. The team 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 tiny genetic variations known as single nucleotide polymorphisms, 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. Those two markers were both from a small region known as 21q on chromosome 6. Both are positioned near a gene known as PRDM1.
The genetic variations closely associated with increased cancer risk, and with each other, appeared to decrease activation of the PRMD1 gene. They had no detectable effect any other genes. 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 any PRDM1.
Other studies have found that PRDM1 is involved in a variety of fundamental cellular processes, including proliferation, differentiation and apoptosis"”which can all go awry in cancer. The gene's activity is lost in many cancer types. In the team's small samples, only three percent of patients with both of the protective variants developed second cancers within 30 years; nearly 33 percent of those with both of the high-risk variations did.
"Taken together, our findings support a novel role for PRDM1 as a radiation-responsive tumor suppressor. PRMD1 may be important for understanding the causes of second cancers in survivors of pediatric Hodgkin's lymphoma as well as in other cancer patients treated with radiation therapy," the authors write.
Dr. Onel hopes this study will "bring some optimism" back to genome-wide association studies. 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. 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," Dr. Onel said.
SOURCE: Nature Medicine, July 22, 2011.