Genetic Variations Help Predict Second Cancer in Pediatric Hodgkin Lymphoma Patients
More than 90% of patients with Hodgkin's lymphoma survive, making is one of the most treatable cancers. Even so, nearly 20% of patients treated as children develop a second cancer within 30 years.
A genome-wide association study published in the August issue of Nature Medicine 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. This knowledge could help physicians tailor treatment to reduce the risks for patients who are most susceptible to long-term damage.
Hodgkin's lymphoma is a cancer of lymph tissue found in the lymph nodes, spleen, liver, bone marrow, and other sites. It is most common among people ages 15 - 35 and 50 - 70. Treatment consists of radiation therapy, chemotherapy, or both, depending on the stage.
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.
"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 Kenan Onel, MD, PhD, associate professor of pediatrics and senior author of the study. "Luckily our options for Hodgkin's are broad enough that we can find ways to control the initial disease without relying on radiation therapy."
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 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 variants 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.
Previous 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 Onel's small samples, only 3% of patients with both of the protective variants developed second cancers within 30 years; nearly 33% of those with both of the high-risk variations did.
"Taken together," the authors note, "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."
Timothy Best, Dalin Li, Andrew D Skol, Tomas Kirchhoff, Sarah A Jackson, Yutaka Yasui, Smita Bhatia, Louise C Strong, Susan M Domchek, Katherine L Nathanson, Olufunmilayo I Olopade, R Stephanie Huang, Thomas M Mack, David V Conti, Kenneth Offit, Wendy Cozen, Leslie L Robison, Kenan Onel. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. Nature Medicine, 2011; DOI: 10.1038/nm.2407
U.S. National Library of Medicine: Hodgkin’s Lymphoma