July 26, 2011 — Hodgkin's lymphoma is one of the most treatable cancers, but pediatric survivors face a high risk for radiation-therapy-induced second malignant neoplasms. In a new development, researchers have identified 2 genetic variations that might predict which patients are most at risk for a secondary cancer in adulthood.
One of their study's take-home messages is that it is possible to obtain results from genome-wide association studies (GWASs), explained Kenan Onel, MD, PhD, associate professor of pediatrics at the University of Chicago, Illinois, and senior author of the study.
Many previous GWASs have found multiple genetic differences, with each of them playing only a modest role and with minimal impact on clinical management. But according to Dr. Onel, the study by he and his colleagues focused on the interaction between genes and a very specific environmental factor — the development of cancer many years after radiation therapy. They found that a small number of genetic differences had a very big impact.
"The idea is that different exposures elicit different cellular responses, each with its own set of genetic determinants," he told Medscape Medical News. "Thus, by not accounting for them in GWASs, you are by definition going to obscure and attenuate disease-related genetic signals."
The study was published online July 24 in Nature Medicine.
Significant Risk for Second Cancers
Although more than 90% of children with Hodgkin's lymphoma survive after undergoing a treatment regimen of radiation and chemotherapy, they remain at a significant risk for a secondary cancer. In the 30 years after their initial treatment, the authors note, the incidence of a radiation-therapy-induced cancer is 18.4%, with an absolute excess risk of 6.9 per 1000 person-years of follow-up.
This high prevalence makes second malignant neoplasms the second leading cause of death among survivors. Primarily affected are organs in the involved mediastinal radiotherapy field, including the thyroid, skin, gastrointestinal tract, and breast (in women). The risk is positively associated with the cumulative radiation dose; the younger the patients are when undergoing treatment, the greater the risk.
The authors point out that despite the clinical importance of this serious late consequence of radiation therapy, very little is known about predisposing risk factors. For that reason, a GWAS was conducted to identify variants associated with radiation-therapy-induced secondary malignancies in Hodgkin's lymphoma survivors. They hypothesized that if they limited their study to survivors who had been treated with radiation therapy, it would improve their power to detect the genetic contribution to the risk for secondary cancers.
The second most important take-home message is that context matters, explained Dr. Onel. "Our SNPs [single-nucleotide polymorphisms] are very common in individuals of European descent — the risk haplotype is present in 50% of such individuals — but they only contribute to cancer risk in the context of radiation exposure."
"Thus, in the absence of exposure information, they will appear neutral in genetic studies and not be identified," he added.
The discovery of the genetic variants could have clinical utility in the future. These data suggest that, overall, the incidence of a second malignancy after radiation therapy is about 18%, Dr. Onel explained. "If a patient has the protective haplotype, the risk is about 3%. If the patient has the risk haplotype, the risk is about 30%."
Although this could have an impact on clinical decision making, right now the numbers are too small and "our confidence intervals are too wide to advocate that this be done," he said. "What we need are more numbers."
There are several challenges to achieving this goal, Dr. Onel pointed out. First is that Hodgkin's lymphoma is a rare disease. Second is that radiation-therapy-induced second cancers occur in only a subset of patients. "Our risk variants seem to be associated with risk for second cancers in Hodgkin's lymphoma patients treated under the age of 20, but not over the age of 20," he said, "and the average time to development of a second cancer is about 20 years."
Study Details
The discovery set consisted of 100 cases of secondary malignancies and 89 control subjects. All cases and controls were diagnosed with Hodgkin's lymphoma as children (median age, 15.6 years) and were treated with 25 to 44 Gy of radiation therapy with or without alkylating chemotherapy. The latency period for secondary malignancies was 20 years; control subjects were followed for at least 27 years.
The authors were able to successfully genotype 665,313 SNPs in 96 of the cases and 82 of the control subjects. The allele frequencies between cases and controls were compared using a χ2 test of homogeneity, and 3 SNPs (rs4946728, rs1040411, and rs8083533) achieved genome-wide significance.
They mapped rs4946728 and rs1040411 to chromosome 6q21, which were intergenic between ATG5 (encoding autophagy protein 5) and PRDM1 (encoding PR domain containing 1, with ZNF domain). PRDM1 encodes a zinc-finger transcriptional repressor involved in a variety of cellular processes, and the authors note that it has recently been shown to be a tumor suppressor in activated B cell–like diffuse large B cell lymphoma. The gene's activity is also lost in many other cancer types.
The authors also found that increasing amounts of risk haplotype — which is comprised of the risk alleles for both rs4946728 and rs1040411 — were significantly associated with lower PRDM1 messenger RNA expression (P = .03). Conversely, there was no association with expression for any other gene, including ATG5 (P = .39).
The next step was to replicate these findings in an independent set of 62 survivors who developed secondary cancers and 71 cancer-free control subjects who were all treated for Hodgkin's lymphoma in childhood with 25 to 44 Gy of mediastinal radiation therapy. There were significant associations between secondary malignancies and both SNPs on chromosome 6q21 — rs4946728 (P = .002) and rs1040411 (P = .03) — but not rs8083533 (P = .82).
Dr. Onel and colleagues also genotyped both SNPs in 57 cases of secondary malignancies and 37 control subjects who were diagnosed with Hodgkin's lymphoma as adults and treated with radiation therapy (median age, 24.0 years). However, there was no association with rs4946728 (P = .87) or rs1040411 (P = .65). Although this suggests that age at radiation therapy exposure modifies the association between these variants and risk, the authors caution that these results be interpreted carefully, given the small number of individuals genotyped.
Future Plans
"The next step is to identify more patients to study so that we can have more confidence in the clinical value of our findings," Dr. Onel explained. "Data from Stanford University suggest that some subsets of patients with Hodgkin's lymphoma can be successfully cured with chemotherapy alone, so there are radiation-therapy-free options."
He speculated that genotyping for the identified variants could conceivably be incorporated into a pre-Hodgkin's lymphoma treatment workup to decide whether or not a patient should receive radiotherapy. "If the patient does need radiation, then the presence of the risk variants may suggest that the patients be closely monitored for second cancer, much the same way as a patient with a BRCA mutation would be followed," he pointed out.
"All of this is in the future of course," he added, "assuming our results stand up to further scrutiny."
The study was funded by the National Institutes of Health, the American Cancer Society, American Lebanese Syrian Associated Charities, the Leukemia Lymphoma Society, the Breast Cancer Research Foundation, the Cancer Research Foundation, and the University of Chicago Comprehensive Cancer Center. The authors have disclosed no relevant financial relationships.
Nat Med. Published online July 24, 2011. Abstract
One of their study's take-home messages is that it is possible to obtain results from genome-wide association studies (GWASs), explained Kenan Onel, MD, PhD, associate professor of pediatrics at the University of Chicago, Illinois, and senior author of the study.
Many previous GWASs have found multiple genetic differences, with each of them playing only a modest role and with minimal impact on clinical management. But according to Dr. Onel, the study by he and his colleagues focused on the interaction between genes and a very specific environmental factor — the development of cancer many years after radiation therapy. They found that a small number of genetic differences had a very big impact.
"The idea is that different exposures elicit different cellular responses, each with its own set of genetic determinants," he told Medscape Medical News. "Thus, by not accounting for them in GWASs, you are by definition going to obscure and attenuate disease-related genetic signals."
The study was published online July 24 in Nature Medicine.
Significant Risk for Second Cancers
Although more than 90% of children with Hodgkin's lymphoma survive after undergoing a treatment regimen of radiation and chemotherapy, they remain at a significant risk for a secondary cancer. In the 30 years after their initial treatment, the authors note, the incidence of a radiation-therapy-induced cancer is 18.4%, with an absolute excess risk of 6.9 per 1000 person-years of follow-up.
This high prevalence makes second malignant neoplasms the second leading cause of death among survivors. Primarily affected are organs in the involved mediastinal radiotherapy field, including the thyroid, skin, gastrointestinal tract, and breast (in women). The risk is positively associated with the cumulative radiation dose; the younger the patients are when undergoing treatment, the greater the risk.
The authors point out that despite the clinical importance of this serious late consequence of radiation therapy, very little is known about predisposing risk factors. For that reason, a GWAS was conducted to identify variants associated with radiation-therapy-induced secondary malignancies in Hodgkin's lymphoma survivors. They hypothesized that if they limited their study to survivors who had been treated with radiation therapy, it would improve their power to detect the genetic contribution to the risk for secondary cancers.
The second most important take-home message is that context matters, explained Dr. Onel. "Our SNPs [single-nucleotide polymorphisms] are very common in individuals of European descent — the risk haplotype is present in 50% of such individuals — but they only contribute to cancer risk in the context of radiation exposure."
"Thus, in the absence of exposure information, they will appear neutral in genetic studies and not be identified," he added.
The discovery of the genetic variants could have clinical utility in the future. These data suggest that, overall, the incidence of a second malignancy after radiation therapy is about 18%, Dr. Onel explained. "If a patient has the protective haplotype, the risk is about 3%. If the patient has the risk haplotype, the risk is about 30%."
Although this could have an impact on clinical decision making, right now the numbers are too small and "our confidence intervals are too wide to advocate that this be done," he said. "What we need are more numbers."
There are several challenges to achieving this goal, Dr. Onel pointed out. First is that Hodgkin's lymphoma is a rare disease. Second is that radiation-therapy-induced second cancers occur in only a subset of patients. "Our risk variants seem to be associated with risk for second cancers in Hodgkin's lymphoma patients treated under the age of 20, but not over the age of 20," he said, "and the average time to development of a second cancer is about 20 years."
Study Details
The discovery set consisted of 100 cases of secondary malignancies and 89 control subjects. All cases and controls were diagnosed with Hodgkin's lymphoma as children (median age, 15.6 years) and were treated with 25 to 44 Gy of radiation therapy with or without alkylating chemotherapy. The latency period for secondary malignancies was 20 years; control subjects were followed for at least 27 years.
The authors were able to successfully genotype 665,313 SNPs in 96 of the cases and 82 of the control subjects. The allele frequencies between cases and controls were compared using a χ2 test of homogeneity, and 3 SNPs (rs4946728, rs1040411, and rs8083533) achieved genome-wide significance.
They mapped rs4946728 and rs1040411 to chromosome 6q21, which were intergenic between ATG5 (encoding autophagy protein 5) and PRDM1 (encoding PR domain containing 1, with ZNF domain). PRDM1 encodes a zinc-finger transcriptional repressor involved in a variety of cellular processes, and the authors note that it has recently been shown to be a tumor suppressor in activated B cell–like diffuse large B cell lymphoma. The gene's activity is also lost in many other cancer types.
The authors also found that increasing amounts of risk haplotype — which is comprised of the risk alleles for both rs4946728 and rs1040411 — were significantly associated with lower PRDM1 messenger RNA expression (P = .03). Conversely, there was no association with expression for any other gene, including ATG5 (P = .39).
The next step was to replicate these findings in an independent set of 62 survivors who developed secondary cancers and 71 cancer-free control subjects who were all treated for Hodgkin's lymphoma in childhood with 25 to 44 Gy of mediastinal radiation therapy. There were significant associations between secondary malignancies and both SNPs on chromosome 6q21 — rs4946728 (P = .002) and rs1040411 (P = .03) — but not rs8083533 (P = .82).
Dr. Onel and colleagues also genotyped both SNPs in 57 cases of secondary malignancies and 37 control subjects who were diagnosed with Hodgkin's lymphoma as adults and treated with radiation therapy (median age, 24.0 years). However, there was no association with rs4946728 (P = .87) or rs1040411 (P = .65). Although this suggests that age at radiation therapy exposure modifies the association between these variants and risk, the authors caution that these results be interpreted carefully, given the small number of individuals genotyped.
Future Plans
"The next step is to identify more patients to study so that we can have more confidence in the clinical value of our findings," Dr. Onel explained. "Data from Stanford University suggest that some subsets of patients with Hodgkin's lymphoma can be successfully cured with chemotherapy alone, so there are radiation-therapy-free options."
He speculated that genotyping for the identified variants could conceivably be incorporated into a pre-Hodgkin's lymphoma treatment workup to decide whether or not a patient should receive radiotherapy. "If the patient does need radiation, then the presence of the risk variants may suggest that the patients be closely monitored for second cancer, much the same way as a patient with a BRCA mutation would be followed," he pointed out.
"All of this is in the future of course," he added, "assuming our results stand up to further scrutiny."
The study was funded by the National Institutes of Health, the American Cancer Society, American Lebanese Syrian Associated Charities, the Leukemia Lymphoma Society, the Breast Cancer Research Foundation, the Cancer Research Foundation, and the University of Chicago Comprehensive Cancer Center. The authors have disclosed no relevant financial relationships.
Nat Med. Published online July 24, 2011. Abstract
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